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

Faecal Incontinence Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01656720
• Other study ID #: NRL001-01/2011 (SEFI)
• Status: Completed
• Phase: Phase 2
• First received: August 1, 2012
• Last updated: June 8, 2015
• Start date: February 2012
• Est. completion date: September 2014

Study information

• Verified date: June 2015
• Source: Norgine
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 417
• Est. completion date: September 2014
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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:

1. 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.

2. 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.

3. Fixed cardiac output states (severe aortic stenosis (AS), hypertrophic obstructive cardiomyopathy (HOCM).

4. Significant mitral regurgitation (MR).

5. 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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Faecal Incontinence
• Fecal Incontinence

Intervention

Drug:
• 1R, 2S-methoxamine hydrochloride

• Placebo

Locations

Country	Name	City	State
Czech Republic	Fakultni Nemocnice BRNO	Brno
Czech Republic	Gastroenterologie S R O	Hradec Kralove
Czech Republic	Krajska Nemocnice Liberec	Liberec
Czech Republic	Fakultni Nemocnice Na Bulovce, Gynekologicko-Porodnicka Klinika	Prague
Czech Republic	Egk S.R.O Sanatoriu< Sv	Praha
Czech Republic	Fakulni Nemocnice Kralovske	Praha
Czech Republic	Fakultni Nemocnice V Motole	Praha
Czech Republic	GEP Clinic S.R.O	Praha
France	Chu Bordeaux - Hopital St Andre	Bordeaux
France	Chu Lyon Groupement Hospitalier Edouard Herriot	Lyon
France	Chu Nantes - Hotel Dieu - Institut Des Maladies De L'Appareil Digestif (IMAD)	Nantes
France	Dr Laurent Siproudhis	Rennes
France	Chu Rouen - Hopital De Charles Nicolle	Rouen
Germany	Martin-Luther-Krankenhaus	Berlin
Germany	Zentrum Fur Darm-Und Beckenchirurgie	Berlin
Germany	Universitats-Frauenklink	Heidelberg
Hungary	PMC Pannon Medical Center	Budapest
Hungary	Polyclinic for Outpatients, Szakrendelo Intezet	Budapest
Hungary	University of Debrecen, Medical and Health Science Center	Debrecen
Hungary	University of Szeged, Albert Szent-Gyorgyi Clinical Center, Faculty of Medicine	Szeged
Hungary	Javorszky Odon Hopsital	Vac Argenti
Hungary	Csolnoky Ferenc Veszprem	Veszprem
Italy	Chirurgia Gastroenterologica	Milan
Italy	Casa Di Cura San Pio X	Milano
Italy	Seconda Unita Operativa Di Chirurgia Generale	Pordenone
Italy	Dipartimento Emergenza Urgenza	Rome
Italy	Unita Operativa Complessa Gastroenteroloogia A	Rome
Italy	Unita Operativa Complessa Patologia Chirurgica A Indirizzo Gastroenterologico	Rome
Poland	Nzoz Vitamed	Bydgoszcz
Poland	General And Proctology Surgeon	Gdow
Poland	Centrum Medyczne, Wyzszej Szkoly Informatycznej	Glowno
Poland	Nzoz Mekmed S.C. Przychondnia Lekarska	Katowice
Poland	Nzoz Mikomed	Lodz
Poland	Osrodek Badawczo - Leczniczy Zbigniew Zegota	Ostroda
Poland	Endoskopia	Sopot
Poland	Lubelskie Centrum Diagnostyczne	Swidnik
Poland	Lecznica Prosen SMO Private Medical Health Care Centre	Warsaw
Poland	Ars Medica SC	Wroclaw
Spain	Hospital Clinic De Barcelona	Barcelona
Spain	Hospital Valle De Hebron	Barcelona
Spain	USP, Hospital De Marbella	Malaga
Spain	Hospital De Mataro	Mataro
Spain	Hospital Clinico Universtiaria Lozana Blesa	Zaragoza
Sweden	Pelvic Floor Centre	Malmo
Sweden	Kirurgiska Kliniken Universitetssjukhuset	Orebro
Sweden	Enheten For Nedre Abdominell Kirurgi	Stockholm
Sweden	Institute of Surgical Sciences	Uppsala
United Kingdom	St Mark's Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	Queens Medical Centre	Nottingham
United Kingdom	Nothern General Hopsital	Sheffield

Sponsors (1)

Lead Sponsor	Collaborator
Norgine

Countries where clinical trial is conducted

Czech Republic,  France,  Germany,  Hungary,  Italy,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	To provide data on the efficacy of NRL001 in patients with faecal incontinence over an 8 week treatment period		8 weeks	No
Secondary	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	No
Secondary	To evaluate the population pharmacokinetics and to establish any pharmacokinetic/pharmacodynamic relationship with adverse events		8 weeks	No
Secondary	To evaluate the dose-response relationship in order to identify the appropriate dose(s) of NRL001 for future studies		8 weeks	No
Secondary	To evaluate the effect of treatment according to the patient's Faecal Incontinence Quality of Life questionnaire at 4 and 8 weeks		8 weeks	No
Secondary	To evaluate the effect of treatment according to the Vaizey score at 4 and 8 weeks		8 weeks	No