A Multi-centre, Phase II, Double-blind, Randomised, Placebo-controlled, Parallel Group, Dose-ranging Study in Patients With Faecal Incontinence; to Evaluate the Efficacy, Safety and Tolerability of Locally Applied NRL001 Over an 8 Week Treatment Period
- Conditions
- Faecal Incontinence
- Interventions
- Drug: 1R, 2S-methoxamine hydrochlorideDrug: Placebo
- Registration Number
- NCT01656720
- Lead Sponsor
- Norgine
- Brief Summary
The purpose of this study is to evaluate the safety, tolerability and efficacy of NRL001 in the treatment of faecal incontinence, compared against placebo
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 417
- 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).
- Diagnosis of faecal incontinence with a Wexner score of 8 - 20 inclusive at Visit 1 - Screening Visit.
- Historical clinical evidence (past 6 months prior to Visit 1 - Screening Visit) of faecal incontinence episodes (solids, liquid, gas or mucus).
- 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.
- Able and willing to receive rectal examinations and treatments.
- Patients must be aged >18 without significant acute or uncontrolled chronic disease.
- 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.
- Female patients must be postmenopausal (for at least one year and confirmed by serum FSH at screening), or surgically sterile, practicing true sexual abstinence, or using Investigator-approved methods of contraception throughout the study until after the post study physical examination and have a negative pregnancy test at screening.
- 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.
- Male patients must not donate sperm during the study and for 90 days after the completion of the study.
- Patients taking any continuous medication need to have been on a stable regimen for at least 1 month prior to Visit 1 - Screening Visit.
-
External anal sphincter disruption related to faecal incontinence caused by trauma.
-
Patients with complicating gastrointestinal (GI) disease including those with inflammatory bowel diseases, patients that have received radiotherapy or surgery for anal cancer, patients with rectal prolapse, transanal surgery.
-
Relevant history of or presence of any significant or uncontrolled cardiovascular risk including:
- 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.
- Abnormal 24 hour Screening Holter: 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.
- Fixed cardiac output states (severe aortic stenosis (AS), hypertrophic obstructive cardiomyopathy (HOCM).
- Significant mitral regurgitation (MR).
- Cardiac failure (New York Heart Association (NYHA) stage II-IV).
-
Severe or uncontrolled asthma or chronic obstructive pulmonary disease determined by clinical history, physical examination, lung function tests or exercise tolerance
-
Chronic liver disease (e.g. liver cirrhosis, chronic hepatitis, severe hepatic insufficiency).
-
Vascular claudication after <50 metres walking distance.
-
Severe renal impairment defined as glomerular filtration rate (GFR) ≤ 30 ml/min, uncontrolled and reno-vascular end stage renal disease.
-
Patients with diabetic polyneuropathies.
-
Any type of chronic diarrhoea or frequent diarrhoea (defined as >5 loose stools per day).
-
Faecal impaction and overflow diarrhoea.
-
Male patients with clinically diagnosed prostatic hyperplasia.
-
Clinically significant electrolyte abnormalities, e.g. clinically significant low/high potassium and low sodium.
-
Presence of clinical symptomatic haemorrhoids (grade III and IV), anal fissures or anorectal fistulas.
-
Less than 2 episodes of faecal incontinence (solids, liquid, gas or mucus) per week during the 4 week historical period prior to Visit 1 - Screening Visit.
-
Participation in a clinical drug study during the 90 days preceding the initial dose in this study.
-
Known history of allergy to methoxamine or any other ingredients of the Investigational Medicinal Product.
-
Patients who, in the opinion of the Investigator, are unsuitable for participation in the study due to any dependencies, general medical conditions or significant illness within two weeks prior to randomisation.
-
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.
-
A personal or family history of QTcf prolongation or sudden death.
-
Patients taking Loperamide (2mg) >8 tablets per day for faecal incontinence either alone or in combination with codeine phosphate and/or paracetamol (8/500mg).
-
Patients using any device for the treatment of faecal incontinence.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description NRL001 5mg 1R, 2S-methoxamine hydrochloride 5mg NRL001 in a 2g suppository Placebo Placebo Placebo 2g Suppository NRL001 10mg 1R, 2S-methoxamine hydrochloride 10mg NRL001 in a 2g suppository NRL001 7.5mg 1R, 2S-methoxamine hydrochloride 7.5mg NRL001 in a 2g suppository
- Primary Outcome Measures
Name Time Method Evaluate the efficacy of NRL001 in faecal incontinence by assessing the improvement of the incontinence status after 4 weeks of treatment compared to baseline by means of the Wexner score Up to 8 weeks
- Secondary Outcome Measures
Name Time Method To provide data on the efficacy of NRL001 in patients with faecal incontinence over an 8 week treatment period 8 weeks To provide preliminary data on the safety and tolerability of NRL001 (5mg, 7.5mg and 10mg) over an 8 week treatment period compared to placebo 8 weeks To evaluate the population pharmacokinetics and to establish any pharmacokinetic/pharmacodynamic relationship with adverse events 8 weeks To evaluate the dose-response relationship in order to identify the appropriate dose(s) of NRL001 for future studies 8 weeks To evaluate the effect of treatment according to the patient's Faecal Incontinence Quality of Life questionnaire at 4 and 8 weeks 8 weeks To evaluate the effect of treatment according to the Vaizey score at 4 and 8 weeks 8 weeks
Trial Locations
- Locations (51)
Dr Laurent Siproudhis
🇫🇷Rennes, France
Dipartimento Emergenza Urgenza
🇮🇹Rome, Italy
Unita Operativa Complessa Patologia Chirurgica A Indirizzo Gastroenterologico
🇮🇹Rome, Italy
Universitats-Frauenklink
🇩🇪Heidelberg, Germany
Chu Lyon Groupement Hospitalier Edouard Herriot
🇫🇷Lyon, France
Polyclinic for Outpatients, Szakrendelo Intezet
🇭🇺Budapest, Hungary
Fakultni Nemocnice Na Bulovce, Gynekologicko-Porodnicka Klinika
🇨🇿Prague, Czech Republic
Chirurgia Gastroenterologica
🇮🇹Milan, Italy
Unita Operativa Complessa Gastroenteroloogia A
🇮🇹Rome, Italy
Chu Nantes - Hotel Dieu - Institut Des Maladies De L'Appareil Digestif (IMAD)
🇫🇷Nantes, France
Chu Rouen - Hopital De Charles Nicolle
🇫🇷Rouen, France
Zentrum Fur Darm-Und Beckenchirurgie
🇩🇪Berlin, Germany
Hospital Clinico Universtiaria Lozana Blesa
🇪🇸Zaragoza, Spain
Fakultni Nemocnice BRNO
🇨🇿Brno, Czech Republic
Egk S.R.O Sanatoriu< Sv
🇨🇿Praha, Czech Republic
Javorszky Odon Hopsital
🇭🇺Vac Argenti, Hungary
Nothern General Hopsital
🇬🇧Sheffield, United Kingdom
General And Proctology Surgeon
🇵🇱Gdow, Poland
University of Debrecen, Medical and Health Science Center
🇭🇺Debrecen, Hungary
Casa Di Cura San Pio X
🇮🇹Milano, Italy
Hospital De Mataro
🇪🇸Mataro, Spain
Martin-Luther-Krankenhaus
🇩🇪Berlin, Germany
Hospital Clinic De Barcelona
🇪🇸Barcelona, Spain
Ars Medica SC
🇵🇱Wroclaw, Poland
University College Hospital
🇬🇧London, United Kingdom
Enheten For Nedre Abdominell Kirurgi
🇸🇪Stockholm, Sweden
Seconda Unita Operativa Di Chirurgia Generale
🇮🇹Pordenone, Italy
Pelvic Floor Centre
🇸🇪Malmo, Sweden
Kirurgiska Kliniken Universitetssjukhuset
🇸🇪Orebro, Sweden
USP, Hospital De Marbella
🇪🇸Malaga, Spain
St Mark's Hospital
🇬🇧London, United Kingdom
GEP Clinic S.R.O
🇨🇿Praha, Czech Republic
Fakultni Nemocnice V Motole
🇨🇿Praha, Czech Republic
Chu Bordeaux - Hopital St Andre
🇫🇷Bordeaux, France
Lubelskie Centrum Diagnostyczne
🇵🇱Swidnik, Poland
Lecznica Prosen SMO Private Medical Health Care Centre
🇵🇱Warsaw, Poland
Hospital Valle De Hebron
🇪🇸Barcelona, Spain
Queens Medical Centre
🇬🇧Nottingham, United Kingdom
Institute of Surgical Sciences
🇸🇪Uppsala, Sweden
Gastroenterologie S R O
🇨🇿Hradec Kralove, Czech Republic
Nzoz Vitamed
🇵🇱Bydgoszcz, Poland
Krajska Nemocnice Liberec
🇨🇿Liberec, Czech Republic
Centrum Medyczne, Wyzszej Szkoly Informatycznej
🇵🇱Glowno, Poland
Endoskopia
🇵🇱Sopot, Poland
PMC Pannon Medical Center
🇭🇺Budapest, Hungary
Fakulni Nemocnice Kralovske
🇨🇿Praha, Czech Republic
University of Szeged, Albert Szent-Gyorgyi Clinical Center, Faculty of Medicine
🇭🇺Szeged, Hungary
Csolnoky Ferenc Veszprem
🇭🇺Veszprem, Hungary
Nzoz Mekmed S.C. Przychondnia Lekarska
🇵🇱Katowice, Poland
Nzoz Mikomed
🇵🇱Lodz, Poland
Osrodek Badawczo - Leczniczy Zbigniew Zegota
🇵🇱Ostroda, Poland