The Effect Of Dose Titration And Dose Tapering On The Tolerability Of DVS SR In Women With Vasomotor Symptoms

Study Overview
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Brief Summary
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Desvenlafaxine succinate (DVS SR) is a serotonin and norepinephrine reuptake inhibitor (SNRI). It is a nonhormonal option for the treatment of Vasomotor Symptoms (VMS) associated with menopause. Nausea is the most common adverse event that is observed in clinical studies and is the main reason for discontinuation during the first week of therapy. Other adverse events (headache, nausea, and dizziness) associated with DVS SR have been noted to occur when subjects abruptly discontinue the medication. The purpose of this study is to evaluate several titration and tapering regimens of DVS SR to ensure a better tolerability profile at the start and completion of treatment. In addition, this study will provide a long posttreatment follow-up to assess any symptoms after treatment is discontinued.

Official Title
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The Effect of Dose Titration and Dose Tapering on the Tolerability of DVS SR in Women With Vasomotor Symptoms Associated With Menopause: The PRIMMUS (PRIstiq for Managing Menopause and Understanding Symptoms) Study

Conditions
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Vasomotor Symptoms

Intervention / Treatment
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* Drug: desvenlafaxine succinate sustained release
* Drug: desvenlafaxine succinate sustained release
* Drug: desvenlafaxine succinate sustained release
* Drug: desvenlafaxine succinate sustained release
* Drug: Placebo
* Drug: desvenlafaxine succinate sustained release
* Drug: desvenlafaxine succinate sustained release
* Drug: desvenlafaxine succinate sustained release


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generally healthy, postmenopausal woman who seeks treatment for hot flushes. Meets 1 of the following: At least 12 months of spontaneous amenorrhea; At least 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL; At least 6 weeks postsurgical bilateral oophorectomy (with or without hysterectomy). Hysterectomized without bilateral oophorectomy and with serum FSH levels >40 mIU/mL. Exclusion Criteria: History of a seizure disorder other than a single childhood febrile seizure. History or presence of clinically important hepatic or renal disease or other medical disease. Presence or recent history of major depressive disorder, bipolar disorder, psychotic disorder, or generalized anxiety disorder requiring therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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 |
| --- | --- |
| Active Comparator: A<br> | Drug: desvenlafaxine succinate sustained release<br>* Titration 100 mg<br>|
| Active Comparator: B<br> | Drug: desvenlafaxine succinate sustained release<br>* Titration 50 mg<br>|
| Active Comparator: C<br> | Drug: desvenlafaxine succinate sustained release<br>* Titration 25 mg, 50mg<br>|
| Active Comparator: D<br> | Drug: desvenlafaxine succinate sustained release<br>* Titration 25 mg<br>|
| Active Comparator: E<br> | Drug: Placebo<br>* Tapering placebo<br>|
| Active Comparator: F<br> | Drug: desvenlafaxine succinate sustained release<br>* Tapering 50 mg, placebo<br>|
| Active Comparator: G<br> | Drug: desvenlafaxine succinate sustained release<br>* Tapering 50 mg, 25 mg<br>|
| Placebo Comparator: H<br> | Drug: desvenlafaxine succinate sustained release<br>* Tapering 50 mg QOD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Nausea During the First 2 Weeks of Treatment | Nausea by spontaneous reports to the investigators was counted if it was reported during first 2 weeks of treatment, and it was not seen before the first dose of treatment, or if it was seen before the first dose and the symptoms got worse. If multiple incidences occurred on the same participant during the 2 weeks, only 1 incidence was counted. | Baseline up to Week 2 | 
| Discontinuation Emergent Signs and Symptoms (DESS) Total Score at the End of First Week of Tapering | DESS: a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. The DESS total score is the sum of the number of new symptoms and old (but worse) symptoms (1) and 0 for old and unchanged symptom, absent, or old symptom but improved for a total possible range of 0 to 43. A higher score indicates more symptoms. | Week 17 | 
| DESS Total Score at End of Second Week of Tapering | DESS: a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. The DESS total score is the sum of the number of new symptoms and old (but worse) symptoms (1) and 0 for old and unchanged symptom, absent, or old symptom but improved for a total possible range of 0 to 43. A higher score indicates more symptoms. | Week 18 | 
| DESS Total Score at 1 Week After the End of Tapering | DESS: a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. The DESS total score is the sum of the number of new symptoms and old (but worse) symptoms (1) and 0 for old and unchanged symptom, absent, or old symptom but improved for a total possible range of 0 to 43. A higher score indicates more symptoms. | Week 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Other Spontaneously Reported Adverse Events (AEs) in First 2 Weeks of Treatment | Any untoward medical occurrence in a participant who received study drug was considered an AE, without regard to possibility of causal relationship. | Baseline up to Week 2 | 
| Percentage of Participants Discontinuing Treatment Due to AEs in First 2 Weeks of Treatment | Any untoward medical occurrence in a participant who received study drug was considered an AE, without regard to possibility of causal relationship. | Baseline up to Week 2 | 
| Number of Participants With Each DESS at the End of First Week of Tapering | DESS: a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. | Week 17 | 
| Number of Participants With Each DESS at the End of Second Week of Tapering | DESS: a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. | Week 18 | 
| Number of Participants With Each DESS One Week After End of Tapering | DESS: a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. | Week 19 | 
| Number of Participants Showing Satisfaction With Tolerability During the First Two Weeks of Treatment | Satisfaction with tolerability (lack of bothersomeness) was assessed using a questionnaire via an interactive voice response system (IVRS)/interactive web based response system (IWRS), and evaluated based on participants' response of extremely satisfied, satisfied, neutral, dissatisfied or extremely dissatisfied with the study medication. | Week 1 and Week 2 | 
| Number of Participants Showing Satisfaction With Tolerability at the End of Tapering | Satisfaction with tolerability (lack of bothersomeness) was assessed using a questionnaire via an IVRS/IWRS and evaluated based on participants' response of extremely satisfied, satisfied, neutral, dissatisfied or extremely dissatisfied with the study medication. | Week 19 | 
| Menopause Symptoms-treatment Satisfaction Questionnaire (MS-TSQ) Score | MS-TSQ is a questionnaire assessing participants' degree of satisfaction with regard to the test article which was administered to the participants via an IVRS/IWRS. The questionnaire comprised 8 questions and each was rated on a scale from 0 (extremely dissatisfied) to 4 (extremely satisfied). | Week 16 | 
| Change From Baseline in Menopause-specific Quality of Life Questionnaire (MenQOL) Score at Week 4, Week 8, Week 12 and Week 16 | MenQOL questionnaire assessed how bothered participants were with 31 symptoms. It contains domains: vasomotor (items 1-3); psychosocial (items 4-10); physical (items 11-26); sexual (items 27-29); in addition to nausea and indigestion. 31 individual symptoms are rated on a scale of 0 (not at all bothered) to 6 (extremely bothered). Total possible score ranged from 0 to 186. MenQOL summary score was calculated as mean of four domain scores (Physical function, Psychosocial function, Sexual function and Vasomotor function) ranging from 1 to 8, with higher scores indicating worse quality of life. | Baseline, Week 4, Week 8, Week 12 and Week 16 |