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Effects of Single Dose Citalopram and Reboxetine on Urethral and Anal Closure Function on Healthy Female Subjects

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ClinicalTrials.gov Identifier: NCT04097288
Recruitment Status : Recruiting
First Posted : September 20, 2019
Last Update Posted : September 25, 2019
Sponsor:
Information provided by (Responsible Party):
Thea Christoffersen, University Hospital Bispebjerg and Frederiksberg

Brief Summary:

This study will investigate if citalopram, a selective serotonin reuptake inhibitor, is reducing the opening pressure of the urethra and possibly causing or worsening stress urinary incontinence. Reboxetine, a norepinephrine reuptake inhibitor, is known to increase urethral opening pressure through actions on adrenoceptors in Onuf´s nucleus and will act as an active control.

Furthermore, this study is performed to explore the effects of reboxetine and citalopram on the opening pressure of the anal canal.


Condition or disease Intervention/treatment Phase
Stress Urinary Incontinence Fecal Incontinence Drug: Citalopram 40mg Drug: Reboxetine 8 mg Drug: Placebo oral tablet Phase 1

Detailed Description:

This study will investigate if citalopram, a selective serotonin reuptake inhibitor, is reducing the opening pressure of the urethra and possibly causing or worsening stress urinary incontinence. Theoretically, citalopram can affect the tone of urethra through actions on serotonergic receptors in Onuf´s nucleus that innervates the striated muscle in urethra. Treatment with selective serotonin reuptake inhibitors is common and has been associated with urinary incontinence. Stress urinary incontinence is frequent and the most common cause of urinary incontinence. Reboxetine, a norepinephrine reuptake inhibitor, is known to increase urethral opening pressure through actions on adrenoceptors in Onuf´s nucleus and will act as an active control. Should the tone of urethra decrease significantly after ingestion of citalopram, this study would contribute to a deeper understanding of stress urinary incontinence and give rise to a debate of pharmacologic treatment of stress urinary incontinence diagnosed in patients treated with citalopram (this debate may also include use of selective serotonin reuptake inhibitor).

Furthermore, this study is performed to explore the effects of reboxetine and citalopram on the opening pressure of the anal canal. Onuf´s nucleus, like the striated urethral sphincter, innervates the striated skeletal muscle of the external sphincter in the anal canal. The prevalence of fecal incontinence (FI) increases with age and is estimated to affect 15% of people aged over 50 years. Pharmacologic treatment of fecal incontinence is very sparse and new treatments it is very desirable. If reboxetine or citalopram increases the anal opening pressure these pharmacologic agents might leads to new ways of treating FI, making this study the first to explore this area.

The design is a single center, randomized, double-blind, placebo controlled, three period cross over phase I study. Twenty-four healthy, female subjects are recruited and investigated during three independent trial days where one of the pharmacologic agents is given each trial day (citalopram, reboxetine or placebo) in concordance with the sequence (order of the pharmacologic agents given). Subjects will be drafted randomly and evenly among the three sequences possible. During all trial days pressures of the urethra and the anal canal of every subject will be measured by urethral pressure reflectometry and anal acoustic reflectometry at the time of maximum plasma concentration of citalopram and reboxetine. A clinically meaningful difference in urethral pressure after administration of citalopram is assessed to be 10 cmH2O compared to placebo (reboxetine acts as an active control) while a clinically meaningful difference in anal pressure after administration of citalopram or reboxetine is assessed to be 15 cmH2O compared to placebo.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Single center, randomized, double-blind, placebo controlled, three period cross over phase I study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Single Dose Citalopram and Reboxetine on Urethral and Anal Closure Function on Healthy Female Subjects
Actual Study Start Date : September 17, 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Single dose citalopram
A blinded single dose 40 mg citalopram is administered three hours before urethral pressure reflectometry and anal acoustic reflectometry measurements
Drug: Citalopram 40mg
Single dose

Active Comparator: Single dose reboxetine
A blinded single dose 8 mg reboxetine is administered two hours before urethral pressure reflectometry and anal acoustic reflectometry measurements
Drug: Reboxetine 8 mg
Single dose

Placebo Comparator: Single dose placebo citalopram
A blinded single dose visually identical placebo pill to citalopram is administered three hours before urethral pressure reflectometry and anal acoustic reflectometry measurements
Drug: Placebo oral tablet
Single dose
Other Name: Placebo to citalopram

Placebo Comparator: Single dose placebo reboxetine
A blinded single dose visually identical placebo pill to reboxetine is administered two hours before urethral pressure reflectometry and anal acoustic reflectometry measurements
Drug: Placebo oral tablet
Single dose
Other Name: Placebo tó reboxetine




Primary Outcome Measures :
  1. Difference in average UOP-placebo and average UOP-citalopram (during relaxation) [ Time Frame: UPR measurements are performed 3 hours after blinded administration of citalopram or placebo to citalopram and two hours after blinded administration of reboxetine/placebo to reboxetine ]
    Difference in urethral opening pressure

  2. Difference in average AOP-placebo and average AOP-citalopram or average AOP-reboxetine (during relaxation) [ Time Frame: UPR measurements are performed 3 hours after blinded administration of citalopram or placebo to citalopram and two hours after blinded administration of reboxetine/placebo to reboxetine ]
    Difference in urethral opening pressure


Secondary Outcome Measures :
  1. Difference in average UOP-placebo and average UOP-reboxetine (during relaxation) [ Time Frame: UPR measurements are performed 3 hours after blinded administration of citalopram or placebo to citalopram and two hours after blinded administration of reboxetine/placebo to reboxetine ]
    Difference in urethral opening pressure

  2. Difference in average UOP-placebo and average UOP-citalopram or UOP-reboxetine (during voluntary contraction) [ Time Frame: UPR measurements are performed 3 hours after blinded administration of citalopram or placebo to citalopram and two hours after blinded administration of reboxetine/placebo to reboxetine ]
    Difference in urethral opening pressure

  3. Difference in average AOP-placebo and average AOP-citalopram or AOP-reboxetine (during voluntary contraction). [ Time Frame: UPR measurements are performed 3 hours after blinded administration of citalopram or placebo to citalopram and two hours after blinded administration of reboxetine/placebo to reboxetine ]
    Difference in urethral opening pressure



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Signed written consent of participation
  • Female
  • Age between 18 and 55 years (both included)
  • Normal weight (BMI 18,5 to 30,0 kg/m2).
  • Regular use of safe contraceptive products ie. Intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long acting injections) through the entire trial and until eight days after the study has ended for the subject (registered at trial day one, two and three). Subjects who are postmenopausal (defined as no menses for 12 months or more prior enrolment) can be included without use of contraceptive products.

Exclusion Criteria:

  • Known hypersensitivity of Citalopram.
  • Known hypersensitivity of Edronax.
  • A history of significant cardiovascular, gastrointestinal, endocrine, hematologic, immunologic, metabolic or genitourologic disease (including pelvic surgery because of trauma, pelvic trauma, lower urinary tract surgery, irradiation to the pelvis, history or evidence of an anatomical anomaly of the lower urinary tract, urinary outlet obstruction, urinary retention, urethral hypermobility , prolapse of pelvic organs, hematuria or urinary tract infection at screening) or lung disease, neurologic, dermatologic, psychiatric disease, kidney disease, malign diseases or other major diseases assessed by the investigator.
  • Known QT-interval prolongation or congenital long QT syndrome
  • History or objective symptoms of urinary incontinence
  • Current infectious disease (fever and symptoms associated with viral or bacterial disease (including respiratory tract infections) or fungal disease (excluding cutaneous infection).
  • Pulse under 40 beats pr. minute or above 100 beats pr. minute. Average systolic blood pressure above 140 mmHg or average diastolic blood pressure over 90 mmHg (average of three measurements performed on screening). In case blood pressure or pulse should deviate from these criteria allowance of three additional measurements are accepted.
  • Current participation in other clinical trials that might affect the results of this trial (judged by the investigators).
  • Use of prescription drugs, over the-counter drugs or herbalism drugs. Exceptions from these criteria are use of paracetamol (4 g a day) and safe contraception as stated above.
  • Current consumption of alcohol above 14 units of alcohol a week.
  • Smoking within three months.
  • Drug abuse within three months.
  • Present pregnancy, at screening or during the trial, including a positive pregnancy test (presented at trial day one, two or three).
  • Breastfeeding at screening or during the study (registered at trial day one, two and three).
  • Any kind of condition (anamnestic or objective) that the investigator assess that must lead to exclusion of this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04097288


Contacts
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Contact: Thea Christoffersen, MD 004560770308 thea.christoffersen@regionh.dk
Contact: Jesper Sonne, DMSc 004538635454 jesper.sonne@regionh.dk

Locations
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Denmark
Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital Recruiting
Copenhagen, Denmark, 2400
Contact: Troels Riis    26600147    troels.riis@regionh.dk   
Sponsors and Collaborators
University Hospital Bispebjerg and Frederiksberg
Investigators
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Principal Investigator: Jesper Sonne, DMSc University Hospital Frederiksberg and Bispebjerg

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Responsible Party: Thea Christoffersen, Investigator, University Hospital Bispebjerg and Frederiksberg
ClinicalTrials.gov Identifier: NCT04097288     History of Changes
Other Study ID Numbers: SSRI-UPR-01
2019-000059-14 ( EudraCT Number )
First Posted: September 20, 2019    Key Record Dates
Last Update Posted: September 25, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Thea Christoffersen, University Hospital Bispebjerg and Frederiksberg:
stress urinary incontinence
pharmacologic treatment
fecal incontinence
Additional relevant MeSH terms:
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Dexetimide
Citalopram
Cholinergic Antagonists
Cholinergic Agents
Fecal Incontinence
Urinary Incontinence
Enuresis
Urinary Incontinence, Stress
Urination Disorders
Urologic Diseases
Lower Urinary Tract Symptoms
Urological Manifestations
Signs and Symptoms
Behavioral Symptoms
Elimination Disorders
Mental Disorders
Rectal Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Reboxetine
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents