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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)

Primary Purpose

Depression

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
MK-8777
Placebo
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Depression focused on measuring randomized, placebo controlled, maximum tolerated dose

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm 5

    Arm 6

    Arm 7

    Arm 8

    Arm 9

    Arm 10

    Arm 11

    Arm Type

    Experimental

    Placebo Comparator

    Experimental

    Placebo Comparator

    Experimental

    Placebo Comparator

    Experimental

    Placebo Comparator

    Experimental

    Experimental

    Placebo Comparator

    Arm Label

    Part 1: Block A MK-8777

    Part 1: Block A Placebo

    Part 1: Block B MK-8777

    Part 1: Block B Placebo

    Part 1: Block C MK-8777

    Part 1: Block C Placebo

    Part 1: Block D MK-8777

    Part 1: Block D Placebo

    Part 2: MK-8777 200 mg

    Part 2: MK-8777 800 mg

    Part 2: Placebo

    Arm Description

    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.

    Participants receive placebo BID for a total of 16 days.

    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.

    Participants receive placebo BID for a total of 13 days.

    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.

    Participants receive placebo BID for a total of 10 days.

    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.

    Participants receive placebo BID for a total of 13 days.

    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.

    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.

    Participants receive placebo BID for 27 days followed by one day of placebo QD. Participants receive placebo for 28 days.

    Outcomes

    Primary Outcome Measures

    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.
    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.
    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).
    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.
    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).

    Secondary Outcome Measures

    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.
    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.

    Full Information

    First Posted
    January 28, 2008
    Last Updated
    October 10, 2018
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00610649
    Brief Title
    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)
    Official Title
    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)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    September 20, 2007 (Actual)
    Primary Completion Date
    November 18, 2008 (Actual)
    Study Completion Date
    December 10, 2008 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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
    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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Depression
    Keywords
    randomized, placebo controlled, maximum tolerated dose

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    54 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Part 1: Block A MK-8777
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Part 1: Block A Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants receive placebo BID for a total of 16 days.
    Arm Title
    Part 1: Block B MK-8777
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Part 1: Block B Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants receive placebo BID for a total of 13 days.
    Arm Title
    Part 1: Block C MK-8777
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Part 1: Block C Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants receive placebo BID for a total of 10 days.
    Arm Title
    Part 1: Block D MK-8777
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Part 1: Block D Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants receive placebo BID for a total of 13 days.
    Arm Title
    Part 2: MK-8777 200 mg
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Part 2: MK-8777 800 mg
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Part 2: Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants receive placebo BID for 27 days followed by one day of placebo QD. Participants receive placebo for 28 days.
    Intervention Type
    Drug
    Intervention Name(s)
    MK-8777
    Intervention Description
    Orally administered capsules containing either 50 mg or 100 mg MK-8777.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Orally administered matching placebo capsules.
    Primary Outcome Measure Information:
    Title
    Part 1: Number of Participants With Moderate Intensity Adverse Events (AEs)
    Description
    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.
    Time Frame
    Up to 7 days following the last dose of study drug (Up to 23 days)
    Title
    Part 1: Number of Participants With Serious Adverse Events (SAEs)
    Description
    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.
    Time Frame
    Up to 30 days following the last dose of study drug (Up to 46 days)
    Title
    Part 1: Number of Participants With AEs Leading to Discontinuation of Study Drug
    Description
    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).
    Time Frame
    Up to the last dose of study drug (Up to 16 days)
    Title
    Part 2: Number of Participants With AEs
    Description
    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.
    Time Frame
    Up to 7 days following the last dose of study drug (Up to 35 days)
    Title
    Part 2: Number of Participants With AEs Leading to Discontinuation of Study Drug
    Description
    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).
    Time Frame
    Up to the last dose of study drug (Up to 28 days)
    Secondary Outcome Measure Information:
    Title
    Part 1: Change From Baseline in the Montgomery-Ashberg Depression Rating Scale (MADRS)
    Description
    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.
    Time Frame
    Baseline and end of treatment (Up to Day 16)
    Title
    Part 2: Change From Baseline in the MADRS
    Description
    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.
    Time Frame
    Baseline and end of treatment (Up to Day 28)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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.

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    34510411
    Citation
    Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021 Sep 12;9(9):CD011612. doi: 10.1002/14651858.CD011612.pub3.
    Results Reference
    derived
    PubMed Identifier
    22954616
    Citation
    Nations KR, Dogterom P, Bursi R, Schipper J, Greenwald S, Zraket D, Gertsik L, Johnstone J, Lee A, Pande Y, Ruigt G, Ereshefsky L. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2012 Dec;26(12):1525-39. doi: 10.1177/0269881112458728. Epub 2012 Sep 6.
    Results Reference
    derived

    Learn more about this trial

    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)

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