Conditions: Urinary Incontinence, Stress Fecal Incontinence
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 16
Healthy volunteers: yes

Brief summary:
A double-blinded, randomized, crossover study in healthy females with placebo and single dose imipramine 50 mg.

Primary objective: Does imipramine increase the tone of the external urethral sphincter? Urethral Opening Pressure (UOP) is measured with Urethral Pressure Reflectometry (UPR). UOP increases correlate with effect in treating stress urinary incontinence. Can imipramine treat stress urinary incontinence? Secondary objective: Does imipramine increase the tone of the anal sphincter? The opening pressure is measured with Anal Acoustic Reflectometry (AAR). The investigators also wish to establish the within-subject standard deviation for AAR to enable power calculations in future studies.

Detailed description:

Arms:
arm 1: A: Imipramine Hydrochloride 25 MG x2 B: Placebo Oral Tablet x2 arm 2: A: Placebo Oral Tablet x2 B: Imipramine Hydrochloride 25 MG x2

Interventions: intervention 1: Placebo Oral Tablet intervention 2: Imipramine Hydrochloride 25 MG
Intervention descriptions: intervention 1: Placebo film coated tablet: Lactose monohydrate, potato starch, gelatine, magnesium stearate, talc intervention 2: Two Imipramin DAK film coated tablets 25 mg each, single dose

Protocol document:
Prot_SAP_000.pdf: 
 
 
                            
 
English translation of the Danish study 
protocol dated 2017-04-18.  
Translated 2019-07-26. 
 
 


 
 
 
  
  
Effect of single dose 
of imipramine on urethral and 
anal sphincter in healthy female subjects 
measured 
by Urethral Pressure Reflectometry (UPR) 
and Anal Acustic Reflectometry (AAR) 
 
Signature of primary investigator 
I've read all the pages in this protocol. I agree to conduct the study under this protocol. I confirm that the 
study will be conducted according to the International Conference on Harmonization (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local law. I will make sure that 
all subinvestigators and other relevant employees have access to copies of this protocol and ICH GCP 
guidelines so they can work according to them. 
 
Main Investigator and Sponsor 
Signature:  
 
  
 


 
 
Collaborators 
Production, labeling, randomization, blinding and packaging of study drugs  
Region Hovedstadens Apotek  
Marielundvej 25, 2730 Herlev  
 
 
Data processing and data analysis  
Chief physician, dr. with. Niels Klarskov  
Department of Gynecology-Obstetrics Department G, Herlev and Gentofte Hospital  
 
 
Monitor 
GCP unit at Copenhagen University  
Hospital Bispebjerg Hospital, Building 51, 3rd floor  
Bispebjerg Bakke 23, 2400 Copenhagen NV  
 
Time schedule 
Expected first visit for first person: Earliest 2017-04-18.  
Expected last visit for the last subject: Latest 2017-12-31. 
 
 


 
 
Contents 
Signature of primary investigator ...................................................................................................................... 2 
Collaborators ..................................................................................................................................................... 3 
Time schedule .................................................................................................................................................... 3 
Abbreviations..................................................................................................................................................... 6 
Summary ............................................................................................................................................................ 7 
Background ........................................................................................................................................................ 8 
Objective ............................................................................................................................................................ 9 
Hypothesis ....................................................................................................................................................... 10 
Purpose ............................................................................................................................................................ 10 
Design .............................................................................................................................................................. 10 
Inclusion criteria .............................................................................................................................................. 10 
Inclusion criteria .............................................................................................................................................. 11 
Recruitment ..................................................................................................................................................... 11 
Reimbursement ............................................................................................................................................... 11 
Procedures ....................................................................................................................................................... 12 
Methods .......................................................................................................................................................... 12 
Statistics ........................................................................................................................................................... 13 
Time schedule .................................................................................................................................................. 13 
Place ................................................................................................................................................................ 13 
Practical opportunities .................................................................................................................................... 13 
Rights ............................................................................................................................................................... 13 
Quality control ................................................................................................................................................. 14 
Ethics ............................................................................................................................................................... 14 
Results ............................................................................................................................................................. 15 
Adverse Events ................................................................................................................................................ 15 
Medical charts ................................................................................................................................................. 18 
Unblinding ....................................................................................................................................................... 18 
Drop out........................................................................................................................................................... 18 
Data ................................................................................................................................................................. 18 
Financing .......................................................................................................................................................... 19 
Budget ............................................................................................................................................................. 19 
Administrative conditions ............................................................................................................................... 19 


 
 
Insurance ......................................................................................................................................................... 19 
Monitoring ....................................................................................................................................................... 19 
References ....................................................................................................................................................... 20 
 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
 


 
 
Abbreviations 
  
5-HT 5-Hydroxytryptamine or serotonine    
AAR Anal Acoustic Reflectometry  
ADR Adverse Drug Reactions      
AE Adverse Events      
CNS Central nervous system            
CRF Case Report Form     
GCP Good Clinical Practice        
ICH International Conference on harmonization          
ON Onuf's Nucleus or Onuf’s core              
RMSE Residual Mean Squared Error              
SAE Serious Adverse Events              
SD Standard Deviation              
SUI Stress Urinary Incontinence              
SUSAR Suspected Unexpected Serious Adverse Reaction              
TCA Tricyclic antidepressants              
TVT Tension free Vaginal Tape              
UOP Urethral Opening Pressure              
UP Urethral Pressure Profilometry              
UPR Urethral Pressure Reflectometry              
  
 
 
 
 


 
 
Summary 
Stress urinary incontinence (SUI) and fecal incontinence are common disorders of the general 
population. Pharmacological treatment can increase sphincter tone for the external urethral sphincter and 
thus better the symptoms of SUI or increase the tone of the external anal sphincter and thus better 
symptoms of feecal incontinence. In Denmark, only one registered medicine exists for the treatment of 
SUI; duloxetine. There is no approved drug for the treatment of fecal incontinence, which acts on 
the tone of the internal or external anal sphincter. We want to investigate an alternative medical treatment 
in the form of imipramine; a tricyclic antidepressant (TCA) with known adverse reactions. Previous studies 
with imipramine have shown varying degrees of efficacy in patients with SUI. Imipramine has never been 
studied in relation to fecal incontinence. Reflectometry is a simple, safe and valid way to assess the 
pressure conditions in the urethra (UPR) and the anal canal (AAR). In total, we will examine 16 healthy 
female subjects in a double-blind, placebo-controlled, crossover study, in which single-dose imipramine 50 
mg or placebo is given. The effect on SUI is assessed by the change in Urethral Opening Pressure (UOP) 
measured by Urethral Pressure Reflectometry (UPR). UOP has previously been shown to be a good 
objective measure, which correlates with the subjective effects of drugs on SUI. UPR requires fewer 
subjects compared to urinary diaries or Urethral Pressure Profilometry (UPP) to find statistically significant 
differences (greater power). In case of change in UOP of more than 10 cm H2 O compared to placebo, the 
effect is clinically relevant and there will be a basis for further studies in relation to reduction 
in urine incontinence episodes, side effects and subjective improvement with imipramine use in patients 
with SUI. This may, in the long term, it may allow medical treatment with imipramine in patients with SUI 
who do not tolerate duloxetine. The Anal Acustic Reflectometry (AAR) measurements are exploratory. We 
will examine the pressure conditions in the anal canal after intake of imipramine 50 mg to assess 
whether imipramine could have a role in the treatment of stool incontinence, and examine the statistical 
variation of AAR, so that it will be possible to estimate the required number of subjects in phase 1 studies in 
which AAR can be used to assess the effect of new drugs against fecal incontinence. 
  
 
 


 
 
Background 
Stress urinary incontinence (SUI):  
SUI is frequent with a prevalence of 30 % to 50% with the highest prevalence from 25 to 49 years of 
age (1). SUI is defined symptomatically as involuntary urine leakage during increased abdominal 
pressure, e.g. by coughing, sneezing, lifting or other physical activity (2). First-line treatment of SUI is 
conservative in terms of weight loss, smoking cessation, pelvic floor training and 
intravaginal devices (pessaries, tampons, etc.).  In case of failure of conservative treatment, surgical 
treatment is offered, and the evidence is solid for mid urethral, suprapubic loosely fixed polypropylene 
slings (TVT, etc.), which can be performed as outpatient interventions in local analgesia (3). 
  
Medical treatment of SUI:  
Drug therapy in patients with pure SUI is generally used only, when surgery is contraindicated, or not 
desired by the patient (3). In Denmark, only one drug, duloxetine, is registered with the indication "stress 
urinary incontinence in women". However, the effect is small and, compared to placebo, only a few percent 
of patients have effect on SUI symptoms (11% versus 8%). Also, the number of incontinence episodes is 
reduced by only approx. 1 pr. day (4). Side effects are frequent, especially side effects from the central 
nervous system (CNS) such as nausea, sleep disorders, nervousness, headache, decreased libido 
and anorgasm (4). Treatment effects and side effects can be assessed within a few weeks and, in the 
absence of efficacy, treatment should be stopped (4). 
  
Fecal Incontinence:  
Fecal incontinence occurs in up to 8% of the general population (5-7). Fecal incontinence is often due to 
decreased function of the internal or external sphincter either due to trauma or degeneration (8). 
  
Medical treatment of fecal incontinence:  
A possible treatment may be to increase the pressure in the anal canal pharmacologically (9). Thus, it has 
been shown that resting pressure measured by anal manometry is increased by local treatment 
with methoxamine (potent adrenergic alpha agonist) (10). Unfortunately, a clinical effect on anal 
incontinence in this topical treatment in a clinical placebo controlled trial (11) has not been demonstrated. 
  
Imipramine in general and side effects:  
We want to investigate an alternative medical treatment in the form of the TCA imipramine. Imipramine is 
approved for the treatment of moderate to severe depression and for enuresis nocturna (urination during 
sleep) (12). Imipramine is an old preparation and has been on the market in Denmark since 1976 (13). The 
side effects are known, and the most frequently observed are dry mouth, dizziness, sexual 
disorders, withdrawal symptoms by abrupt discontinuation, myoclonus, confusion and blurred vision (13). 
  
Imipramine - pharmacodynamics: 
Imipramine affects the catecholamine metabolism in the CNS. Imipramine is a potent inhibitor of 
noradrenaline and serotonin (5 - HT) reuptake by the presynaptic, noradrenergic nerve 
endings. Imipramine is one of the least sedative TCAs and has only moderate antimuscarinic activity (13).  
 
  
Imipramine - pharmcokinetics: 
Imipramine is rapidly and completely absorbed from the gastrointestinal tract after oral administration, 
and the plasma concentration peak within 1 hour. Imipramine undergoes first pass metabolism in the liver 
to the primary, active metabolite, desimipramine via the enzyme CYP2C19. Imipramine is eliminated 
mainly in the urine and the half-life is 6 to 18 hours - that is to say all imipramine is eliminated after 


 
 
approx. 4 days if liver and kidney function is normal. 
 
  
Imipramine and SUI: 
Imipramine has previously been used for the treatment of SUI. There is, however, no randomized 
studies that illustrate the efficacy and side effects (3), but two smaller studies have described a positive 
effect on the number of urinary incontinence episodes, and the pressure profile in the urethra measured by 
UPP (14,15). The mode of action of treating SUI is unknown (3). Rat studies have shown that immediately 
following imipramine administration the threshold for the vesicourethral micturition reflex on CNS level is 
increased, whereby emptying of the bladder is inhibited. Similarly, cat studies have shown that stimulation 
of 5-HT receptors modifies spinal reflexes, which are involved in bladder control. Onuf’s nucleus 
(ON), located at the sacral part of the medulla spinalis, contains the motor neurons that control the activity 
of the external urethral sphincter. ON is affected by both serotonergic and noradrenergic nerve cells. Thus, 
it is pharmacodynamically plausible that an increased concentration of norepinephrine and serotonine in 
the synaptic cleft by imipramine administration may affect the bladder and the external utrethral sphincter, 
so that the bladder emptying is inhibited (16). 
  
Imipramine and Stool Incontinence: 
The striated external sphincter of the anal canal, like the urethral sphincter, 
is innervated by ON (17). Theoretically, TCAs could increase the maximum squeeze pressure and, to a lesser 
degree, the resting pressure. In an older, uncontrolled study, amitriptyline (another TCA) had clinical effect 
on stool incontinence (18). In this study, in addition to reduced intestinal peristalsis, increased resting and 
squeezing pressure in the anal canal was also measured. The squeeze pressure increased from 108 cm H2 O 
to 123 cm H2 O, which, however, was statistically insignificant. A pressure increase of 15 cmH2O or more is 
probably clinically relevant. It has been shown that opening pressures at rest and during squeeze measured 
with AAR correlate with severity of stool incontinence, while the same does not apply to rest and squeeze 
pressure measured by conventional manometry (19). It is therefore possible, that AAR can provide a more 
reliable assessment of new pharmaceuticals for the treatment of fecal incontinence. Variation between the 
predose measurements and the changes in the placebo period can clarify whether AAR is suitable for phase 
1 studies, and can be as a basis for sample size calculations for future studies. 
  
Imipramine dose and time for UPR and AAR: 
Imipramine will be administered as a single 50 mg dose, which is the recommended starting dose for 
treatment with imipramine (12). UPR will be performed 1 hour after tablet intake, corresponding to the 
time for peak plasma concentration, tmax (13). AAR will be performed immediately after UPR. 
  
Objective 
We will examine, whether imipramine increases the resistance of the external, urethral sphincter, and 
hence whether imipramine could have a role in the medical treatment of SUI, where there currently exists 
only on medication on the Danish market with this indication. 
Exploratory, we will investigate if imipramine increases the resistance of the anal canal, and thus 
if imipramine could have a role in the medical treatment of fecal incontinence. We will investigate the 
variation in the measurements of AAR, and thus whether AAR can be used for future phase 1 studies 
with pharmacological treatment of fecal incontinence and allow sample size calculations for such studies. 
  


 
 
Hypothesis 
The 0-hypothesis is that there is no difference in UOP in healthy subjects before and after single-dose 
placebo and single-dose imipramine 50 mg. The alternative hypothesis is that imipramine single dose 
increases UOP with a minimum of 10 cm H2 O over placebo. 
  
Explorative hypotheses for AAR measurements: 
1) Anal Acustic Reflectometry can be used to test pharmaceuticals with effect on the internal and 
external anal sphincter.      
2) Imipramine has an effect on the anal opening pressure during squeeze.      
  
Purpose 
The aim is investigate whether imipramine has a role in the medical treatment of SUI and / or faecal 
incontinence and to assess whether AAR in the future can be used for phase 1 trials for pharmaceuticals 
against fecal incontinence. 
  
Design 
The study is a placebo-controlled, double-blind, randomized, crossover study. We recruit 16 healthy 
female subjects and investigate them on two different trial days preceded by a screening day. 
The participants are recruited and called for an information day, where written and oral information is 
given. Subsequently, there is the possibility of reflection time (up to 7 days) before signing written 
consent. When the written consent is signed, the participants are summoned for the screening day, when 
the inclusion criteria and the exclusion criteria are reviewed incl. objective examination by doctor and 
measurement of resting blood pressure. If inclusion criteria are fulfilled and none of the exclusion 
criteria are met included the participant and assigned a blinded medication kit. On the same day (if consent 
is given immediately) or the second day (if time is needed before signing the consent), trial day 1 is 
performed; see under procedures. There is a wash out period of minimum 7 days between trial day 1 and 
trial day 2. Five days after trial day 2, the participants are called by to identify and follow-up 
any Adverse Events (AE). 
Production of placebo, packaging, blinding, randomization and labeling is handled by Region Hovedstadens 
Apotek according to GMP. Region Hovedstadens Apotek produces 16 medicine kits consisting of placebo 
and imipramine. Medicine kits are randomized by Region Hovedstadens Apotek. Each medicine kit is 
assigned one randomization number from 1 to 16. Of these 16 medicine kits, 8 will  contain placebo on trial 
day 1 and imipramine on trial day 2, and 8 medicine kits will contain imipramine on trial day 1 and placebo 
on trial day 2. The contents of the medicine kits are blinded to everyone involved until data collection is 
completed (unless individual subjects are unblinded based on side effects). When trial participants 
are included they are assigned a randomization number: First test participant gets number 1, next 
participant gets number 2 etc. This corresponds to the a randomization number on the medicine kit from 
which the patient receives trial medication. In addition, 4 extra medicine kits are produced which can be 
used in the event of a dropout. 
Inclusion criteria 
- Signed informed consent.          
- Healthy.          
- Woman.          
- Non-smoking.          


 
 
- Age 18 years to 55 years, both inclusive.          
- Normal weight, ie. BMI 18.5 to 30.0 kg / m2. Weight minimum 50 kg.          
- Consent not to breastfeed during the study or 1 week after the study.          
- Negative pregnancy test on trial day 1 and trial day 2.          
- Consent not to get pregnant during the study.          
- Consent not to participate in other clinical trials concurrently with this study.          
Inclusion criteria 
- Known hypersensitivity to imipramine.          
- history of significant cardiovascular, gastrointestinal, endocrinologic, haematologic, immunological, 
metabolic or genitourological disease (incl. surgery after pelvic trauma, urethral hypermobility or 
prolapse of the organs of the pelvis), pulmonary disease, neurological disease, dermatological disease, 
psychiatric disease, kidney disease, malignant disease and / or other major diseases assessed by 
the investigator.          
- History of or symptoms of urinary incontinence.          
- Treatment of infection at least one week before trial day 1, ie. fever or symptoms of viral infection, 
bacterial infection (including upper respiratory tract infection) or fungal infection (not cutaneous).          
- Clinically significant findings assessed on clinical study on screening day.          
- Pregnant.          
- Pulse <40 or> 100 beats per minute. Mean systolic blood pressure> 140 mmHg or mean diastolic blood 
pressure> 90 mmHg (average of 3 measurements on screening day). If blood pressure or heart rate 
differs from this, an additional 3 measurements can be performed.          
- Prescription drugs or over-the-counter or natural remedies at least 2 weeks before trial day 1 and trial day 
2. Exclusive paracetamol up to 2 g / day and exclusive contraception.          
- Smoking 3 months before trial day 1 and trial day 2.          
- Alcohol consumption, ie. > 14 drinks per week within 3 months before the trial day 1 
and experimental day 2.          
- Substance abuse within 3 months before trial day 1 and trial day 2.          
- Any condition that allows the investigator not to include the subject.          
Recruitment 
Healthy volunteers from previous UPR trials in Zelo Phase-1 unit, which have expressed interest in 
participating in future UPR studies will be informed about the trial and have the opportunity to contact 
us for inclusion. If there are not recruited enough subjects this way, we will recruit with advertisement 
on www.forsøgsperson.dk. All recruitment - and the information - must be approved by the Regional 
Research Ethics Committee. 
  
Reimbursement 
Allowance of DKK 125 per hour and DKK 1000 in nuisance bonus for the UPR measurements and AAR 
measurements on trial day 1 and trial day 2. Thus, compensation of DKK 250 is granted for information day 
and screening day (approximately 2 hours), DKK 1375 for trial day 1 (3 hours and 1000 DKK nuisance 
bonus) and 1375 DKK for trial day 2 (3 hours and 1000 DKK nuisance bonus). A total of DKK 3000 in 
allowance if the entire trial is carried out.  The reimbursement must also be authorized by the Regional 
Research Ethics Committee. 
  


 
 
Procedures 
Information day: Subjects receive written and oral information about the trial. The subject is entitled to an 
assessor. Total approx. 30 minutes duration. The subject is offered reflection time, but if the subject is 
ready to sign written consent, the next part is done immediately. 
  
Screening day: Written consent is obtained. An objective examination is carried out and the medical history 
and information about the consumption of medicine incl. herbal remedies and supplements are 
obtained. Objective examination by doctor. Blood pressure x3 is measured after 5 minutes of rest in a 
supine position. Total approx. 1 hour duration. 
  
Trial day 1: Pregnancy is excluded by pregnancy test via urine sample. The subject is randomized to one of 
the 16 prefabricated, blinded medicine kits. The subject’s bladder is emptied by 
sterile disposable catherization and then 150 ml of 9% NaCl are instilled the bladder. UPR is performed with 
10 measurements, while the subject is relaxing the pelvic floor. Then 5 measurements while the subject is 
squeezing the pelvic floor. Measurements in the urethra are followed by measurements in the anal 
canal, where also 10 measurements are made while the subject is relaxed, and 5 measurements while the 
subject squeeze in the pelvic floor. The subject consumes two tablets according to the randomization and 
trial day. This will be either two placebo tablets or two tablets of Imipramin DAK 25 mg. The subject relaxes 
for 1 hour. Again, the bladder is emptied by sterile disposable catherization and then the bladder is filled 
with 150 ml of 9% NaCl followed by UPR with 10 measurements, while the subject relaxes the pelvic 
floor, then 5 measurements while the subject squeezes the pelvic floor. The measurements in the urethra 
are followed by measurements in the anal canal, where also 10 measurements are made while the subject 
is relaxed, and 5 measurements while the subject is squeezing the pelvic floor. After that, any AE and ADR 
are registered. Total approx. 3 hours duration. 
  
Trial day 2 : Minimum 1 week after trial day 1 to ensure elimination of the drug. Procedure is identical 
to trial day 1. Total approx. 3 hours duration. 
  
A total of 4 days of total approx. 8 hours duration. 
  
Methods 
UPR  
UPR is a validated method for simultaneously measuring the pressure ratio and the cross-
sectional area of the urethra. A very thin and very flexible polyurethane bag is introduced into 
the urethra. Sound waves measure the cross-sectional area of the urethra while pumping air into 
the polyurethane bag, thereby providing knowledge of the pressure in the urethra. The opening and closing 
pressure, opening and closing elasticity and the hysteresis can thus be measured by UPR. UPR is more 
reproducible, with lower variability (and therefore greater statistical power), compared to UPP (20,21). No 
risk or complication of the procedure has been demonstrated beyond limited discomfort by catheter 
insertion and a minor risk of cystitis, which, however, is minimized by sterile technique. 
AAR  
Anal Acoustic Reflectometry (AAR) is a reproducible method of simultaneously measuring pressure and 
cross-sectional area in the anal canal (22). It has been shown that opening pressure at rest and during 
squeeze measured with AAR correlates with severity of fecal incontinence, while the same does not apply 
to rest and squeeze pressure measured by conventional manometry (19). AAR are performed with the 
same equipment and catheters as used in UPR. No risk or complications of the study have been 
demonstrated beyond limited discomfort by having catheters inserted into the anal canal.  


 
 
Statistics 
Power calculation: 
The primary endpoint is the difference (delta) in average baseline UOP and 1-hour UOP. A clinical 
relevant delta between placebo and imipramine is estimated to be 10 cm H2 O. From previous UPR studies 
of pharmacological intervention vs. placebo there was a residual mean squared error (RMSE) of 5.4 for 
measurement of UOP (20) - this corresponds to the standard deviation (SD) of the difference in UOP 
measurements. This gives Cohen's d of 10/5.4 ≈ 1.85. We will investigate 16 subjects to minimize the risk of 
type II errors. For un-paired t-test, Cohen's d = 1.85, α = 0.05 and n = 16 , we have strength = 99% to detect 
a clinically relevant difference of 10 cm H 2 O (23). 
Power calculation for AAR:  
For a sample size of 16 subjects. A clinically relevant difference of 15 cm H 2 0 in pinch opening pressure, SD 
of 21 for squeeze opening pressure (22), alpha of 0.05, gives a power of 80%. 
Results presentation 
Baseline characteristics (age and weight) of trial participants are summarized with mean and SD. 
The results from UPR and AAR are described descriptively with mean and SD. Specifically, within-subject SD 
for AAR is also described to allow future sample size calculations. 
The UOP and opening pressure of the anal sphincter for placebo / imipramine are analyzed according 
to Grizzle’s method for cross-over studies (24), that is with a CROS test: One unpaired, two-sided t-test to 
assess the effect of the intervention. A p value < 0.05 is deemed statistically significant and an average 
difference greater than 10 cm H2 O for UPR and 15 cm H2 O for AAR are deemed clinically significantly. 
  
Time schedule 
Enrollment begins when the necessary permits are available and continue with inclusion until 16 subjects 
are examined according to this Protocol. 
Expected first trial day for first subject: Earliest 18/4 2017. 
Expected last test day for last test subject: No later than 31/12 2017. 
  
Place 
The experiment will take place in the Zelo phase 1 unit, entrance 11B at Bispebjerg Hospital, Bispebjerg 
Bakke 23, 2400 Copenhagen NV. 
  
Practical opportunities 
The Zelo Phase 1 Unit and the associated Department of Clinical Pharmacology have extensive experience 
in performing clinical trials. The UPR measurements and the AAR measurements will be performed by a 
nurse trained and experienced in performing this procedure. 
  
Rights 
Sponsor and primary investigator with overall responsibility is doctor Jonatan Kornholt. 


 
 
Subinvestigator is the chief physician, Dr. med. Jesper Sonne, chief physician dr. med. Niels 
Klarskov and doctor, PhD David Peick Sonne. 
UPR is performed by the nurse Troels Riis. 
Data is stored and processed by the chief physician, dr. med. Niels Klarskov in accordance with 
the approval. 
All results - both positive and negative - will be applied for as soon as possible in a scientific journals. We 
expect to publish two articles; one about UPR and one about AAR. 
The author order for article one will be: Jonatan Kornholt, David Peick Sonne, Troels Riis, Jesper Sonne and 
Niels Klarskov. 
The author order for the second article is : Jonatan Kornholt, David Peick Sonne, Troels Riis, Jesper Sonne 
and Niels Klarskov. 
  
Quality control 
Consent will be obtained from the trial subjects that third parties (e.g. inspector from the Scientific Ethics 
Committee / Data Inspectorate / The Danish Medicines Agency / GCP ) can gain access to health 
information. 
  
Ethics 
The project is carried out in accordance with the ICH-GCP. The project is approved by the Regional Research 
Ethics e Committee, the Data Protection Agency and the Danish Medicines Agency. The study will be 
monitored by the GCP (Good Clinical Practice Unit ). The study will, prior to the inclusion of 
subjects, register in the Clinical Trials Database. 
  
Information and consent 
Subjects are informed both in writing and orally about the purpose and content of the project – in 
accordance with the recommendations of the Scientific Ethics Committee. The subjects are also given the 
folder "Trial subjects’ rights in a health science research project " from the Central Science Ethics 
Committee. 
The first meeting is an information interview with one of the doctors responsible for the trial. Here, 
the subject will be informed orally and given written information. The person in question has the right to 
bring along an assistant. The meeting will take place in quiet undisturbed locations with time for 
questions. The information itself deals with the experiment and its advantages and disadvantages and must 
be easily understood by the subject. 
The subject is informed about the right to refuse information about significant health conditions. The 
informing doctor is responsible for ensuring that the information is understood. The subject then has the 
right to a minimum of one-week reflection time. 
On the screening day, written consent is obtained from the subject. At the declaration of consent, 
the investigator of the trial notes that written and oral information is given as stated above. 
The subjects are informed that they may withdraw their commitment to participate in the trial at any time 
without this having any effect on current or subsequent treatment or controls. 
The subject is informed if, in the course of the experiment, significant information about his or her health 
condition arises he/she will be informed of this, unless the subject explicitly states that he does not want 
this information. 


 
 
Results 
When the results of the study are available, one of the project's doctors will if possible inform the 
participating subjects about the result. Information on the participating subjects are protected under 
the Act on processing of personal data and the Law on patients' rights . 
Side effects and risks 
Sterile disposable catherization and UPR and AAR measurement results in immediate discrete discomfort 
during measurement and minimal risk of developing cystitis, which is minimized by sterile technique. 
  
The side effects of imipramine are well known (12) . The known side effects of imipramine are available in  
the Summary of Product Characteristics 4.8. 
 
The psychiatric and cardiac side effects are considered irrelevant in relation to a single dose. Possible 
adverse reaction are expected to primarily be anticholinergic (e.g. dry mouth, dizziness, and hypotension) 
and hypersensitivity reactions such rash and urticaria. 
  
Pregnancy 
Imipramine does not appear to be associated with an increased risk of malformations (25–27). There is a 
risk of withdrawal symptoms associated with delivery. The subjects are screened for pregnancy with 
pregnancy test (urine) prior to both test days. Only single-dose low dose (50 mg) imipramine is given. It is 
therefore assessed that there is no risk if pregnancy occurs immediately after the trial day, since the 
concentration of the drug is reduced to approx. 6- 40% (half-life 6-18 hours) of the dose and because 
maximum dose is already low, and as the substance has not been shown to be teratogenic in spite of the 
high usage for many years. 
  
Pros and cons 
Disadvantages: Possible side effects of the study drug (though low dose and single dose), low risk of cystitis 
associated with UPR (minimized by sterile technique), and discomfort associated with UPR and 
AAR (transient nuisance) . 
Advantages: The subjects will have no immediate advantage by participating in this trial. The participants 
contribute to the gathering of useful new knowledge about the effect of the trial drug on the pressure in 
the urethra and the anal canal. This can be beneficial for future patients with stress urinary incontinence 
and fecal incontinence. 
Adverse Events 
All Adverse Events are registered on the CRF at the following times: 
• At the end of trial day 1 and trial day 2. 
• At the start of the trial day 2 (AEs since trial day 1). 
• Five days (corresponding to > 5 half-lives) after the last test day (contact by phone). 
Any SAE ( Serious Adverse Events), is immediately (within 24 hours ) reported to the sponsor (Jonatan 
Kornholt) according to the SOP for this. All AEs are followed until they are completed - also beyond the 
duration of the trial. AE is terminated when the subject is in normal health or stable 
condition. All AE, Adverse Drug Reactions (ADR), Serious Adverse Reactions (SAR), Serious Adverse Events 
(SAE) and Suspected Unexpected Serious Adverse Reactions (SUSAR) are handled in accordance with ICH-
GCP and applicable legislation (from the Danish Medicines Agency): 


 
 
"The sponsor must immediately notify the Danish Medicines Agency if, during the trial, unexpected and 
serious suspected adverse reactions (Suspected Unexpected Serious Adverse Reactions , SUSARs ) 
are observed, cf. 2. No. 1. 
The definitions are as follows, cf. the Executive Order on clinical trials: 
• incident: any undesirable event in a patient or subject in a clinical trial after treatment with a drug, 
without necessarily being related to this treatment and the adverse event 
• side effect: any harmful and undesirable reaction to a test drug regardless of dose 
• Unexpected side effect: an adverse reaction whose nature or severity does not correspond to the 
product information (eg, the Investigators- Brochure for an unapproved test drug or the SPC, in the 
case of an approved product) 
• Serious event or serious side effect: An event or side effect, which, regardless of dose, results in 
death, is life-threatening, involves hospitalization or hospitalization, results in significant or persistent 
disability or incapacity for work or leads to congenital anomaly or malformation. 
Reference is made to the guideline in the area:  
Guideline for reporting adverse reactions arising from clinical trials ( Detailed guidance 
on collection , verification and presentation of adverse event / reaction reports arising from clinical trials on 
medicinal products for human use (CT 3)). These guidelines can be found on the Commission website under 
"Volume 10".  
 
Sponsor's obligations 
Pursuant to section 89 (1) of the Danish Medicines Act. 2, no. 1, the sponsor must immediately notify the 
Danish Medicines Agency if there are unexpected and serious suspected adverse reactions during the trial. 
The sponsor must ensure that any information on unexpected and serious suspected adverse reactions 
(SUSAR) that is fatal or life-threatening is recorded and reported to the Drug Administration as soon as 
possible and within 7 days of the knowledge of such a suspected adverse reaction. 
Within 8 days of the report, the sponsor must notify the Danish Medicines Agency of all relevant information 
about the sponsor's and investigator's follow-up to the report. 
All other unexpected and serious suspected adverse reactions must be reported to the Danish Medicines 
Agency no later than 15 days after the sponsor has been informed of these. 
Any report must be accompanied by comments on any implications for the trial. 
(...) 
All adverse reactions and events are reported at the end of the trial in the final report to the Danish 
Medicines Agency. 
Investigator's obligations 
Furthermore, the investigator has the following obligations, cf. the Order for Clinical 
Trials: Investigator must immediately report any serious incidents to the sponsor, with the exception of the 
serious events identified in the trial protocol or investigator brochure as events that do not require 
immediate reporting. 


 
 
The report must be followed up by a detailed written report, and in both the immediate reporting and in the 
subsequent report, the investigator must identify the subjects with a personal code number. 
Investigator must also report to the sponsor events and / or abnormal analysis results that are stated as 
critical to the safety of the subjects in the trial protocol. 
The alert must be in accordance with the rules and deadlines set out in the Protocol. When reporting deaths, 
the investigator must provide any additional information requested by the sponsor. 
The Sponsor / Sponsor Investigator is required to report any suspected serious or unexpected adverse drug 
reactions. 
In order for a side effect to meet the reporting requirement, the side effect must be serious, ie. resulting in 
death, life-threatening, hospitalization or prolongation of hospitalization, resulting in significant or 
persistent disability or incapacity or leading to congenital anomaly or malformation. 
In addition, the side effect must be related to the test drug. In other words, it would say that it is supposed 
to be a causal link between the intake of the drug and the side effect that has occurred. 
Both investigator and sponsor (or sponsor investigator) must assess causality. 
The sponsor must not, therefore, disclose the investigator's assessment, why reports where the sponsor 
does not agree with the investigator should still be reported. 
The side effect should be unexpected, which is a side effect whose nature or severity does not match the 
product information (eg Investigators Brochure for an unapproved test drug or the SPC if it is an approved 
drug). 
If the serious side effect is not listed in this product information, it is considered unexpected. 
In the case of a blinded trial, the assessment of the adverse reaction must be made before blinding. From 
blinded trial, all SUSAR then unblinded before reporting to the authorities. 
Follow-up reports (follow up) should only be submitted if applicable. What information is relevant or not 
should be based on a medical and scientific assessment. " 
Reference document  
The reference document for imipramine is the Summary of Product Characteristics for Imipramine "DAK". 
Annual report  
As the trial lasts for less than 1 year, no annual report is submitted, but at the end of the trial, the final 
report is submitted in accordance with applicable legislation. From the Danish Medicines Agency: 
"After the end of the trial, the sponsor must, within 90 days of the end of the trial, inform the Danish 
Medicines Agency that the trial has been completed by Schedule for completion of clinical trials . (...)    
As soon as possible and no later than 1 year thereafter, the test result must be entered in EudraCT. The data 
will then be published on www.clinicaltrialsregister.eu. This replaces that the trial result must be 
submitted to us [the Danish Medicines Agency]. You can see more here how to enter the results 
in EudraCT . As data becomes publicly available, there will in future not be a requirement to submit a 
publication to us. (...) " 


 
 
Medical charts 
Only healthy subjects are recruited for the trial, and therefore no records will be created or will be 
recorded during the study. CRF is documented instead. 
Unblinding 
Participants’ study medication is always unblinded if SUSAR occurs. If other adverse events occur, 
the investigator or treating doctor will decide if unblinding is needed. Unblinding is done by 
the investigator (or subinvestigator): They open the envelope with the number corresponding to the 
subject's randomization number (stored envelopes are locked in the phase-1 unit where the experiment 
takes place). The envelopes contain information about the given test drug; whether placebo is given day 1 
or day 2 and if there is given imipramine day 1 or day 2. Sponsor is informed of unblinding by person or 
telephone. 
Drop out 
In case of drop out, the reason must be registered on the CRF. If the cause is AE, this is followed until AE is 
complete - beyond the duration of the trial. AE is complete when the patient is in normal health again or 
the condition is stable.  
As a rule, there is not unblinding on drop out, unless the cause for drop out is one of the situations 
specified in the section “Unblinding”. All subject that drop out are offered a telephone call 5 days after 
intake of trial medication to detect any AE.  
Data from drop out is not analyzed, as the analysis is performed as balanced crossover study (see statistics 
section). We recruit and therefore include trial subjects until a total of 16 participants have completed the 
trial, ie. both trial day 1 and trial day 2. When recruiting subjects after the first 16, calls are made to Region 
Hovedstadens Apotek in relation to which medicine kit the next subject must consume; to preserve the 
balanced design and to maintain blinding. 
Data 
On screening day, personal data, incl. CPR number, inclusion and exclusion criteria, medical history and any 
findings by objective examination on Case Report Form (CRF) made for this purpose. On trial day 1 and trial 
day 2, the date, results of the pregnancy test, subject ID, time for the intake of tablets, and time for UPR - 
and AAR measurements, and any AE. Data from the UPR measurement is electronic and transferred to 
encrypted USB key and from there to the data logged folder according to the approval of the Data 
Protection Agency. 
  
Data storage 
Data from UPR and AAR up are kept in anonymous form on PC, to which only the data-
processing personal have access. All files are placed in a locked cabinet, to which only the data 
controller has access. Data is stored for 5 years, after which data is deleted. Envelopes with data on blinded 
medicine are delivered from Region Hovedstadens Apotek together with the medicine kits and stored 
together with Trial Master File and CRF locked in office at Zelo Phase-1 Unit.  
 
Data controllers & data processors 
Primary data manager and data processor: Chief physician, dr. med. Niels Klarskov, Department of 
Gynecological-Obstetrics, Herlev and Gentofte Hospital. 
Secondary data processor: Doctor Jonatan Kornholt, Department of Clinical Pharmacology, Bispebjerg 
Hospital. 


 
 
Financing 
The trial is funded by the Department of Clinical Pharmacology's research funds. 
  
Budget 
Price 
Subject reimbursements 
3,000 DKK * 16 subjects = 48,000 DKK 
Manufacture and packaging of medicine 
11,000 DKK in starting fee  
300 DKK * 20 medicine kit = 6,000 DKK  
Total 17,000 DKK 
Application to The Danish Medicines Agency 
7,734 DKK 
Total 
72,734 DKK 
  
Administrative conditions 
The study is performed according to current legislation and ICH-GCP. The study must be approved by 
the Danish Medicines Agency, the Regional Science Ethics Committee and the Data Protection Agency. The 
study is monitored by the GCP. 
  
The study is carried out in collaboration between the Department of Clinical Pharmacology (Bispebjerg 
Hospital), the Zelo Phase 1 unit (Bispebjerg Hospital) and the Gynecological-Obstetrics Department G 
(Herlev and Gentofte Hospital). 
Contact person Clinical Pharmacological Department (Bispebjerg Hospital): Doctor Jonatan Kornholt. 
Contact person Zelo Phase 1 unit (Bispebjerg Hospital): Chief physician , dr. med. Jesper Sonne. 
Contact person Gynækologisk-Obstetisk Afdeling G (Herlev and Gentofte Hospital): Chief physician, 
dr. med. Niels Klarskov. 
  
Insurance 
Injuries to healthy subjects are covered by both the Patient Statement and the Labor Market Business 
Insurance. All areas of the Danish health service and all authorized healthcare professionals are covered by 
a publicly funded compensation scheme. The scheme covers if the patient is injured in connection with 
treatment in a public hospital, a private hospital, with his or her doctor, with a specialist doctor or with 
other privately-practiced authorized healthcare professionals. “Patients” also include people who 
participate in health science trials. The insurance also covers drug damage. It is the duty of 
the investigator to inform the subject about the insurance available if a drug injury occurs in a subject. 
Monitoring 
The experiment is monitored by the GCP unit at Copenhagen University Hospital. The trial participants 
consent that the GCP unit and the Danish Medicines Agency, as required, can monitor and make audits on 
all data incl. source data. 


 
 
 
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