safety and tolerability of the twice daily intra-anal application of nrl001 cream for 14 days

Conditions: Faecal Incontinence

Summary: the study is being conducted to evaluate the safety and tolerability after single and repeated twice daily intra-anal applications of 1ml nrl001 cream in stepwise increasing concentrations.

single-centre, randomised, placebo-controlled, double-blind, repeated dose study in healthy male and female volunteers, comprising up to six sequential dose groups receiving 1 ml doses of an investigational cream formulation containing 0.50, 0.75, 1.00, 1.50, 2.00 and 2.50% w/w nrl001. doses were to be investigated in stepwise increasing fashion. progression to a higher dose-step required completion of the previous dose-step without safety limiting findings. each dose-step was to be investigated in 12 subjects; in each dose-group, subjects assigned to active treatment were to be studied in parallel with subjects assigned to placebo in double-blind fashion with random (9:3) treatment assignment. each subject was to be studied for one study period with double-blind investigational treatment (1 ml of an investigational cream formulation containing nrl001 or matched placebo) twice daily from the morning of d01 to the afternoon of d14; this phase was to be preceded by a single-blind placebo control day (d-1) with administration of placebo in the morning and afternoon.

Eligibility criteria:
inclusion criteria: * males or females (only females of non-child-bearing potential or of child-bearing potential while taking medically appropriate contraception) * caucasian * 35 to 60 years of age (included) * bmi: between 22 and 26 kg.m-2 * bw: between 50 and 100 kg * willing and able to provide written informed consent exclusion criteria: general - all subjects * previous participation in the trial * participation in any other trial during the last 90 days * donation of blood or plasma within the last 90 days before recruitment * history of any clinically relevant allergy * presence of acute or chronic infection * presence or history of any relevant medical condition or disease (as evaluated on the basis of medical history, physical examination, recumbent and standing blood pressure, treadmill ergometry, clinical laboratory tests \[haematology, clinical chemistry, urinalysis, serology\]) * presence or history of migraine, frequent headaches, raynaud phenomenon, urinary urge, signs and symptoms of prostatism * presence or history of regular/habitual diarrhoea or constipation; previous anal surgery or trauma, anal fissures, rectal disorders * resting systolic blood pressure \> 145 or \ 95 or \< 50 mmhg * positive treadmill ergometry test * resting pulse (pr) or electrocardiographic heart rate (hr) \< 55 bpm * ecg: av-block (av-block grade i included), qt \> 480 msec, qtc \> 450 msec, sick-sinus syndrome * positive hepatitis (hbs-ag or hbc-ab, hcv-ab) or hiv serology test * history of alcohol or (social) drug abuse * positive alcohol or urine drug test * daily consumption of \> 30 g alcohol * smoking more than 15 cigarettes/day or equivalent of other tobacco products * use of prohibited medication * suspicion or evidence that the subject is not reliable * suspicion or evidence that the subject is not able to make a free consent or to understand the information detailed in the subject information sheet. all females * positive pregnancy test * lactating * premenopausal women : not using contraception which is judged adequate and sufficient in the opinion of the clinical investigator