Clinical trial NCT01656720: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Faecal Incontinence
Keywords: Faecal Incontinence
Suppository
Wexner score
Lead sponsor: Norgine
Sponsor class: INDUSTRY
First posted: 2012-08-03
Enrollment: 417
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: Up to 8 weeks
Secondary outcomes:
measure: To provide data on the efficacy of NRL001 in patients with faecal incontinence over an 8 week treatment period
timeFrame: 8 weeks
measure: 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
timeFrame: 8 weeks
measure: To evaluate the population pharmacokinetics and to establish any pharmacokinetic/pharmacodynamic relationship with adverse events
timeFrame: 8 weeks
measure: To evaluate the dose-response relationship in order to identify the appropriate dose(s) of NRL001 for future studies
timeFrame: 8 weeks
measure: To evaluate the effect of treatment according to the patient's Faecal Incontinence Quality of Life questionnaire at 4 and 8 weeks
timeFrame: 8 weeks
measure: To evaluate the effect of treatment according to the Vaizey score at 4 and 8 weeks
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Brno
country: Czech Republic
facility: Fakultni Nemocnice BRNO
city: Hradec Kralove
country: Czech Republic
facility: Gastroenterologie S R O
city: Liberec
country: Czech Republic
facility: Krajska Nemocnice Liberec
city: Prague
country: Czech Republic
facility: Fakultni Nemocnice Na Bulovce, Gynekologicko-Porodnicka Klinika
city: Praha
country: Czech Republic
facility: Fakulni Nemocnice Kralovske
city: Praha
country: Czech Republic
facility: Egk S.R.O Sanatoriu< Sv
city: Praha
country: Czech Republic
facility: GEP Clinic S.R.O
city: Praha
country: Czech Republic
facility: Fakultni Nemocnice V Motole
city: Bordeaux
country: France
facility: Chu Bordeaux - Hopital St Andre
city: Lyon
country: France
facility: Chu Lyon Groupement Hospitalier Edouard Herriot
city: Nantes
country: France
facility: Chu Nantes - Hotel Dieu - Institut Des Maladies De L'Appareil Digestif (IMAD)
city: Rennes
country: France
facility: Dr Laurent Siproudhis
city: Rouen
country: France
facility: Chu Rouen - Hopital De Charles Nicolle
city: Berlin
country: Germany
facility: Zentrum Fur Darm-Und Beckenchirurgie
city: Berlin
country: Germany
facility: Martin-Luther-Krankenhaus
city: Heidelberg
country: Germany
facility: Universitats-Frauenklink
city: Budapest
country: Hungary
facility: PMC Pannon Medical Center
city: Budapest
country: Hungary
facility: Polyclinic for Outpatients, Szakrendelo Intezet
city: Debrecen
country: Hungary
facility: University of Debrecen, Medical and Health Science Center
city: Szeged
country: Hungary
facility: University of Szeged, Albert Szent-Gyorgyi Clinical Center, Faculty of Medicine
city: Vac Argenti
country: Hungary
facility: Javorszky Odon Hopsital
city: Veszprem
country: Hungary
facility: Csolnoky Ferenc Veszprem
city: Milano
country: Italy
facility: Casa Di Cura San Pio X
city: Milan
country: Italy
facility: Chirurgia Gastroenterologica
city: Pordenone
country: Italy
facility: Seconda Unita Operativa Di Chirurgia Generale
city: Rome
country: Italy
facility: Dipartimento Emergenza Urgenza
city: Rome
country: Italy
facility: Unita Operativa Complessa Gastroenteroloogia A
city: Rome
country: Italy
facility: Unita Operativa Complessa Patologia Chirurgica A Indirizzo Gastroenterologico
city: Bydgoszcz
country: Poland
facility: Nzoz Vitamed
city: Gdow
country: Poland
facility: General And Proctology Surgeon
city: Glowno
country: Poland
facility: Centrum Medyczne, Wyzszej Szkoly Informatycznej
city: Katowice
country: Poland
facility: Nzoz Mekmed S.C. Przychondnia Lekarska
city: Lodz
country: Poland
facility: Nzoz Mikomed
city: Ostroda
country: Poland
facility: Osrodek Badawczo - Leczniczy Zbigniew Zegota
city: Sopot
country: Poland
facility: Endoskopia
city: Swidnik
country: Poland
facility: Lubelskie Centrum Diagnostyczne
city: Warsaw
country: Poland
facility: Lecznica Prosen SMO Private Medical Health Care Centre
city: Wroclaw
country: Poland
facility: Ars Medica SC
city: Barcelona
country: Spain
facility: Hospital Valle De Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic De Barcelona
city: Malaga
country: Spain
facility: USP, Hospital De Marbella
city: Mataro
country: Spain
facility: Hospital De Mataro
city: Zaragoza
country: Spain
facility: Hospital Clinico Universtiaria Lozana Blesa
city: Malmo
country: Sweden
facility: Pelvic Floor Centre
city: Orebro
country: Sweden
facility: Kirurgiska Kliniken Universitetssjukhuset
city: Stockholm
country: Sweden
facility: Enheten For Nedre Abdominell Kirurgi
city: Uppsala
country: Sweden
facility: Institute of Surgical Sciences
city: London
country: United Kingdom
facility: St Mark's Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
city: Sheffield
country: United Kingdom
facility: Nothern General Hopsital
Study officials:
affiliation: Hopital Pontchaillou
name: Laurent Siproudhis, MD
role: PRINCIPAL_INVESTIGATOR
References: