Dose-Finding Safety and Efficacy Trial of Org50081 (Esmir... | NCT00560833

NCT00560833

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description
46101	Other Identifier	Organon Study Number
MK-8265-012	Other Identifier	Merck Study Number
2004-000469-36	EudraCT Number

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	Participants receive placebo, encapsulated tablets, orally (PO), once daily (QD) for up to 12 weeks	Drug: Placebo
Esmirtazapine 2.25 mg	Experimental	Participants receive esmirtazapine 2.25 mg, encapsulated tablets, PO, QD for up to 12 weeks	Drug: esmirtazapine
Esmirtazapine 4.5 mg	Experimental	Participants receive esmirtazapine 4.5 mg, encapsulated tablets, PO, QD for up to 12 weeks	Drug: esmirtazapine
Esmirtazapine 9 mg	Experimental	Participants receive esmirtazapine 9 mg, encapsulated tablets, PO, QD for up to 12 weeks	Drug: esmirtazapine
Esmirtazapine 18 mg	Experimental	Participants receive esmirtazapine 18 mg, encapsulated tablets, PO, QD for up to 12 weeks	Drug: esmirtazapine

Name	Type	Description	Arm Group Labels	Other Names
esmirtazapine	Drug		Esmirtazapine 18 mg Esmirtazapine 2.25 mg Esmirtazapine 4.5 mg Esmirtazapine 9 mg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4	Participants recorded the frequency of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.	Baseline and Week 4
Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12	Participants recorded the frequency of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.	Baseline and Week 12
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4	Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12	The WHQ is a 36-item, user-friendly, and rapid way of assessing nine domains of physical and emotional health for mid-aged women. Participants self-administered the WHQ questionnaire; scoring is based on a 4-point scale as follows: 'Yes definitely=1', 'Yes sometimes=2', 'No not much=3' and 'No not at all=4'. Each score is transformed to a value '1' for scores '1' and '2' and to a value '0' for scores '3' and '4'. Vasomotor symptoms encompass Items 19 and 27 of the 36 total items. The transformed sums of items 19+27 are divided by 2 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

postmenopausal women, defined as:
12 months of spontaneous amenorrhea;
OR 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone

(FSH) levels >40 mIU/mL;

OR 6 weeks post surgical bilateral oophorectomy with or without hysterectomy.
In case the menopausal status of a subject was unclear because of a hysterectomy, the serum FSH level had to be >40 mIU/mL. If the date of the last menstruation was not clear because of perimenopausal hormone use, then the subject had to have a serum FSH level >40 mIU/mL after completion of a washout period (see exclusion criteria below); be >= 40 and <= 65 years of age;
have a body mass index (BMI) >= 18 and <= 32 kg/m^2;
minimum of 7 moderate to severe hot flushes per day or 50 per week, as quantified from daily diary recordings during at least 7 days preceding randomization to trial medication;
able to handle the electronic diary device after training and having at least 80% compliance on complete daily diary entries during the period prior to randomization;
give voluntary written Informed Consent (IC) after the scope and nature of the investigation had been explained, before screening evaluations.

Exclusion Criteria:

history or presence of any malignancy, except non-melanoma skin cancers
any clinically unstable or uncontrolled renal, hepatic, endocrine,

respiratory, hematological, neurological, cardiovascular, or cerebrovascular disease that would put the subject at safety risk or mask measure of efficacy

history of seizures or epilepsy; history or presence of clinically significant depression or other psychiatric disorder which, in the opinion of the investigator, might compromise or confound the participant's participation in the trial; abnormal clinically relevant vaginal bleeding
any clinically relevant (opinion of investigator) abnormal finding during physical, gynecological and breast examination at screening; abnormal, clinically significant results of mammography. Mammography had to have been performed within the last 9 months prior to screening, otherwise it had to be done before inclusion into the trial. For non-US sites, if local laws or guidelines did not allow or advise such frequent mammograms, the documented local laws or guidelines were to be followed; abnormal cervical smear test results (corresponding to Pap III and higher, including Low-Grade Squamous Intraepithelial Lesion (LSIL), High-Grade Squamous Intraepithelial Lesion (HSIL), Cervical Intraepithelial Neoplasia (CIN) 1 and higher). A cervical smear had to have been performed within the last 9 months prior to screening, otherwise it had to be done before inclusion into the trial; hematological or biochemical values at screening outside the reference ranges considered clinically relevant in the opinion of the investigator
high blood pressure (BP) (sitting systolic BP >170 mmHg and/or diastolic BP >100 mmHg)
use of any drug product containing estrogens, progestins, androgens, or tibolone prior to screening (and up to and including randomization) within specified time frames

PubMed Identifier	Type	Citation	Retractions
30712391	Result	Birkhaeuser M, Bitzer J, Braat S, Ramos Y. Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials. Climacteric. 2019 Jun;22(3):312-322. doi: 10.1080/13697137.2018.1561664. Epub 2019 Feb 4.

ID	Type	URL	Comment
	CSR Synopsis	View IPD

Arm/Group Information

ID	Title	Description
FG000	Placebo	Participants receive placebo, encapsulated tablets, orally (PO), once daily (QD) for up to 12 weeks
FG001	Esmirtazapine 2.25 mg	Participants receive esmirtazapine 2.25 mg, encapsulated tablets, PO, QD for up to 12 weeks
FG002	Esmirtazapine 4.5 mg	Participants receive esmirtazapine 4.5 mg, encapsulated tablets, PO, QD for up to 12 weeks
FG003	Esmirtazapine 9 mg	Participants receive esmirtazapine 9 mg, encapsulated tablets, PO, QD for up to 12 weeks
FG004	Esmirtazapine 18mg	Participants receive esmirtazapine 18 mg, encapsulated tablets, PO, QD for up to 12 weeks

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Placebo	Participants receive placebo, encapsulated tablets, orally (PO), once daily (QD) for up to 12 weeks
BG001	Esmirtazapine 2.25 mg	Participants receive esmirtazapine 2.25 mg, encapsulated tablets, PO, QD for up to 12 weeks

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4

Participants recorded the frequency of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

The intent-to-treat (ITT) population, defined as all randomized particpants having at least one recorded pre-baseline value of the number of moderate and severe hot flushes.

Posted

Mean

Standard Deviation

Number of events

Baseline and Week 4

ID	Title	Description

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Participants receive placebo, encapsulated tablets, orally (PO), once daily (QD) for up to 12 weeks

ID	Term
D003984	Dibenzazepines
D006575	Heterocyclic Compounds, 3-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds