| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bowel (faecal) incontinence |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016092 |
| E.1.2 | Term | Faecal incontinence |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of NRL001 in faecal incontinence (FI) by assessing the improvement of the incontinence status after 4 weeks of treatment compared to baseline by means of the Wexner score. |
|
| E.2.2 | Secondary objectives of the trial |
-To provide data on the efficacy of NRL001 in patients with faecal incontinence over an 8 week treatment period
- To provide preliminary data on the safety and tolerability of NRL001 (5mg, 7.5mg and 10 mg) over an 8 week treatment period compared to placebo.
- To evaluate the population pharmacokinetics and to establish any pharmacokinetic/pharmacodynamic relationship with adverse events.
- To evaluate the dose-response relationship in order to identify the appropriate dose(s) of NRL001 for future studies.
- To evaluate the effect of treatment according to the patient's Faecal Incontinence Quality of Life questionnaire at 4 and 8 weeks.
- To evaluate the effect of treatment according to the Wexner
score at 8 weeks.
- To evaluate the effect of treatment according to the Vaizey score at 4 and 8 weeks.
- To evaluate the effect of treatment according to the EQ-5D 5L Healthcare Questionnaire at 4 and 8 weeks.
- To evaluate the overall assessment of patient satisfaction. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.An ultrasound assessment of the internal anal sphincter within the previous 12 months confirming an intact circular internal sphincter with minimal scars (maximum 60 degrees scarring circumferentially).
2.Diagnosis of faecal incontinence with a Wexner score of 8 – 20 inclusive at Visit 1 - Screening Visit.
3.Historical clinical evidence (past 6 months prior to Visit 1 – Screening Visit.) of faecal incontinence episodes (solids, liquid, gas or mucus).
4.Greater than or equal to two faecal incontinence episodes (solids, liquid, gas or mucus) per week during the 4 week historical period prior to Visit 1 – Screening Visit and
during the screening period (between Visit 1 – Screening
Visit and Visit 2 – Randomisation Visit).
5.Able and willing to receive rectal examinations and treatments.
6.Patients must be aged >18 without significant acute or uncontrolled chronic disease.
7.Patients must understand the purpose and risks of the study and be able to provide written informed consent and willing, able and competent to complete the entire study and comply with study instructions as defined in the protocol.
8. Female patients must be postmenopausal (for at least one year and confirmed by serum FSH at screening), or surgically sterile (status post bilateral tubal occlusion, bilateral oophorectomy, or hysterectomy). Female patients of childbearing potential must be practicing one of the following methods of birth control and agrees to continue with this regimen throughout the study period:
• Oral, implantable, or injectable contraceptives (for a minimum of 3 months before study entry) in combination with a condom;
• Intrauterine device in combination with a condom;
• Double barrier method (condoms, sponge, diaphragm,
or vaginal ring with spermicidal jellies or cream);
• True sexual abstinence; and have a negative urine pregnancy test at Visit 1 – Screening Visit.
9.Sexually active male patients must use condoms with their partners throughout the study and for 90 days after completion of the study in addition to their partner’s normal mode of contraception.
10.Male patients must not donate sperm during the study and for 90 days after the completion of the study.
11.Patients taking any continuous medication need to have been on a stable regimen for at least 1 month prior to Visit 1 – Screening Visit.
12. Patients using any medical device for faecal incontinence:
a. that completely occlude the anal canal e.g. anal plug, must stop using the device for at least 8 weeks prior to Visit 1 – Screening Visit
b. which do not occlude the anal canal e.g. sacral nerve stimulation device, bulking agents must continue to use the device in the same way throughout the clinical study period provided that all other inclusion/exclusion criteria are satisfied and that the
patient has been using the device for at least 1 month prior to Visit 1 – Screening Visit.
c. which are implanted and can be deactivated e.g. sacral nerve stimulation device are included. Patients who choose not to use the device during the clinical study must stop using the device for at least 8 weeks prior to Visit 1 – Screening Visit.
13. Patients who are capable of understanding the nature, significance and implications of the clinical study and of making an informed decision based on the information provided.
|
|
| E.4 | Principal exclusion criteria |
1.External anal sphincter disruption related to faecal incontinence caused by trauma.
2.Patients with complicating gastrointestinal (GI) disease including those with active inflammatory bowel diseases (e.g. Crohn´s disease, ulcerative colitis), patients that have received radiotherapy or surgery for anal cancer, patients with rectal prolapse, transanal surgery.
3.Relevant history of or presence of any significant or uncontrolled cardiovascular risk including:
a.Systolic > 160mmHg or Diastolic > 100mmHg. Patients on a stable regimen for > 3 months with controlled hypertension prior to Visit 1 – Screening Visit (Systolic < 140mmHg or Diastolic < 90mmHg) can be included.
b.Clinically significant abnormal 24 hour Screening Holter and/or ECG, corrected QT interval (QTcf) prolongation with cut-off values of >460 ms for females and >430 ms for males, acute arrhythmia, nocturnal bradycardia with heart rate (HR) < 40bpm, atrial fibrillation, AV block Type II and III, Sick Sinus Syndrome, vasovagal syncope.
c.Fixed cardiac output states (severe aortic stenosis (AS), hypertrophic obstructive cardiomyopathy (HOCM).
d.Significant mitral regurgitation (MR).
e.Cardiac failure (New York Heart Association (NYHA) stage II-IV).
4.Severe or uncontrolled asthma or chronic obstructive pulmonary disease determined by clinical history, physical examination, lung function tests or exercise tolerance.
5.Chronic liver disease (e.g. liver cirrhosis, chronic hepatitis, severe hepatic insufficiency).
6.Vascular claudication after <50 metres walking distance.
7.Severe renal impairment defined as glomerular filtration rate (GFR) ≤ 30 ml/min, uncontrolled and reno-vascular end stage renal disease.
8.Patients with diabetic polyneuropathies.
9.Any type of chronic diarrhoea or frequent diarrhoea (defined as > 5 loose stools per day)
10.Faecal impaction and overflow diarrhoea.
11.Male patients with clinically diagnosed and symptomatic prostatic hyperplasia.
12.Clinically significant electrolyte abnormalities, e.g. clinically significant low/high potassium or low sodium.
13.Presence of clinical symptomatic haemorrhoids (grade III and IV), anal fissures or anorectal fistulas.
14.Less than 2 episodes of faecal incontinence episodes (solids, liquid, gas or mucus) per week during the 4 week historical period prior to Visit 1 – Screening Visit and during the screening period (between Visit 1 – Screening Visit and Visit 2 – Randomisation Visit).
15.Participation in a clinical drug study during the 90 days preceding the initial dose in this study.
16.Known history of allergy to methoxamine or any other ingredients of the Investigational Medicinal Product.
17.Patients who, in the opinion of the Investigator, are unsuitable for participation in the study due to any dependencies, medical conditions or significant illness within two weeks prior to randomisation.
18.Use of any disallowed concomitant medication or other medication that the Investigator believes may affect the study including over-the-counter (OTC) products within 30 days prior to the Investigational Medicinal Product administration.
19.A personal or family history of QTcf prolongation or sudden death.
20.Patients taking Loperamide (2mg) >8 tablets per day for faecal incontinence either alone or in combination with codeine phosphate and/or paracetamol.
21. Patients who suffer from closed-angle glaucoma or patients with other diseases with light sensitivity and/or mydriasis.
22. Patients with uncontrolled hyperthyroidism 1 month prior
to Visit 1 – Screening Visit.
23. Females who are breast feeding.
24. Protected adults under guardianship, trusteeship or committed to an institution by governmental or juridical
order.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is defined as the change in Wexner score at Visit 4 – 4 Week Treatment Visit compared to baseline score obtained on Visit 1 – Screening Visit. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 4 Week Treatment Visit (Visit 4) vs. baseline score obtained on Visit 1 (screening visit) |
|
| E.5.2 | Secondary end point(s) |
1. Change in the mean number of faecal incontinence episodes (defined as any leakage/seepage from the anus of gas, mucus, liquid stool or solid stool) in the week prior to the 4 Week Treatment Visit compared to baseline, where the baseline is the last week prior to randomisation.
2. Responder analysis based on a ≥50% reduction in faecal incontinence episodes in the week prior to the 4 and 8 week visits compared to baseline, where baseline is the last week prior to randomisation.
3. Responder analysis based on a ≥30% reduction in faecal incontinence episodes in the week prior to the 4 and 8 week visits compared to baseline, where baseline is the last week prior to randomisation.
4. Responder analysis based on a ≥20% reduction in faecal incontinence episodes in the week prior to the 4 and 8 week visits compared to baseline, where baseline is the last week prior to randomisation.
5. Change in Quality of Life as measured via the FIQoL scale after 4 and 8 weeks of treatment from baseline (Visit 1- Screening Visit).
6. Change in the Wexner score after 8 weeks of treatment from baseline (Visist 1- Screening Visit).
7. Change in the Vaizey score after 4 and 8 weeks of treatment from baseline (Visit 1- Screening Visit).
8. Change in the EQ-5D-5L Healthcare Questionnaire after 4
and 8 weeks of treatment from baseline (Visit 1 – Screening
Visit).
9. Overall assessment of patient satisfaction.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week prior to 4 week visit vs. baseline evaluated the last week prior to randomisation.
2. Week prior to the 4 and 8 week visits vs. baseline evaluated the last week prior to randomisation.
3. Week prior to the 4 and 8 week visits vs. baseline evaluated the last week prior to randomisation.
4. Week prior to the 4 and 8 week visits vs baseline evaluated the last week prior to randomisation.
5. At 4 and 8 weeks of treatment from baseline (Visit 1 - Screening Visit).
6. At 8 weeks of treatment from baseline (Visit 1 - Screening Visit).
7. At 4 and 8 weeks of treatment from baseline (Visit 1 - Screening Visit).
8. At 4 and 8 weeks of treatment from baseline (Visist 1 - Screening Visit)
9. At 7 days post Visit 5 - Final Visit/Premature Termination Visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Quality of life assessment
Assessment of patient satisfaction
Patient reported Healthcare Questionnaire |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different dosage of NRL001 - 5mg/2g, 7.5mg/2g or 10mg/2g |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of this study is defined as 7 days after Last Patient Last Visit (LPLV), i.e. after the last patient has been followed up by a scheduled phone call. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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