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

Primary Purpose

Stress Urinary Incontinence, Fecal Incontinence

Status

Completed

Phase

Phase 1

Locations

Denmark

Study Type

Interventional

Intervention

Citalopram 40mg

Reboxetine 8 mg

Placebo oral tablet

About this trial

This is an interventional treatment trial for Stress Urinary Incontinence focused on measuring stress urinary incontinence, pharmacologic treatment, fecal incontinence

Eligibility Criteria

18 Years - 55 Years (Adult)FemaleAccepts Healthy Volunteers

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.

Sites / Locations

Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Single dose citalopram

Single dose reboxetine

Single dose placebo citalopram

Single dose placebo reboxetine

Arm Description

A blinded single dose 40 mg citalopram is administered three hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

A blinded single dose 8 mg reboxetine is administered two hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

A blinded single dose visually identical placebo pill to citalopram is administered three hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

A blinded single dose visually identical placebo pill to reboxetine is administered two hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

Outcomes

Primary Outcome Measures

Difference in average UOP-placebo and average UOP-citalopram (during relaxation)

Difference in urethral opening pressure

Difference in average AOP-placebo and average AOP-citalopram or average AOP-reboxetine (during relaxation)

Difference in urethral opening pressure

Secondary Outcome Measures

Difference in average UOP-placebo and average UOP-reboxetine (during relaxation)

Difference in urethral opening pressure

Difference in average UOP-placebo and average UOP-citalopram or UOP-reboxetine (during voluntary contraction)

Difference in urethral opening pressure

Difference in average AOP-placebo and average AOP-citalopram or AOP-reboxetine (during voluntary contraction).

Difference in urethral opening pressure

Full Information

NCT ID

NCT04097288

First Posted

May 21, 2019

Last Updated

June 8, 2021

Sponsor

University Hospital Bispebjerg and Frederiksberg

1. Study Identification

Unique Protocol Identification Number

NCT04097288

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Completed

Study Start Date

September 17, 2019 (Actual)

Primary Completion Date

February 1, 2020 (Actual)

Study Completion Date

May 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Hospital Bispebjerg and Frederiksberg

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Stress Urinary Incontinence, Fecal Incontinence

Keywords

stress urinary incontinence, pharmacologic treatment, fecal incontinence

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Model Description

Single center, randomized, double-blind, placebo controlled, three period cross over phase I study

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single dose citalopram

Arm Type

Experimental

Arm Description

A blinded single dose 40 mg citalopram is administered three hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

Arm Title

Single dose reboxetine

Arm Type

Active Comparator

Arm Description

A blinded single dose 8 mg reboxetine is administered two hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

Arm Title

Single dose placebo citalopram

Arm Type

Placebo Comparator

Arm Description

A blinded single dose visually identical placebo pill to citalopram is administered three hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

Arm Title

Single dose placebo reboxetine

Arm Type

Placebo Comparator

Arm Description

A blinded single dose visually identical placebo pill to reboxetine is administered two hours before urethral pressure reflectometry and anal acoustic reflectometry measurements

Intervention Type

Drug

Intervention Name(s)

Citalopram 40mg

Intervention Description

Single dose

Intervention Type

Drug

Intervention Name(s)

Reboxetine 8 mg

Intervention Description

Single dose

Intervention Type

Drug

Intervention Name(s)

Placebo oral tablet

Other Intervention Name(s)

Placebo to citalopram

Intervention Description

Single dose

Intervention Type

Drug

Intervention Name(s)

Placebo oral tablet

Other Intervention Name(s)

Placebo tó reboxetine

Intervention Description

Single dose

Primary Outcome Measure Information:

Title

Difference in average UOP-placebo and average UOP-citalopram (during relaxation)

Description

Difference in urethral opening pressure

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

Title

Difference in average AOP-placebo and average AOP-citalopram or average AOP-reboxetine (during relaxation)

Description

Difference in urethral opening pressure

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

Secondary Outcome Measure Information:

Title

Difference in average UOP-placebo and average UOP-reboxetine (during relaxation)

Description

Difference in urethral opening pressure

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

Title

Difference in average UOP-placebo and average UOP-citalopram or UOP-reboxetine (during voluntary contraction)

Description

Difference in urethral opening pressure

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

Title

Difference in average AOP-placebo and average AOP-citalopram or AOP-reboxetine (during voluntary contraction).

Description

Difference in urethral opening pressure

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

10. Eligibility

Sex

Female

Gender Based

Yes

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jesper Sonne, DMSc

Organizational Affiliation

University Hospital Frederiksberg and Bispebjerg

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital

City

Copenhagen

ZIP/Postal Code

2400

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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