Safety and Tolerability of the Twice Daily Intra-anal Application of NRL001 Cream for 14 Days

Double-blind, Placebo-controlled, Randomised, Parallel-group Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacodynamic Effects and Pharmacokinetics of Twice Daily Intra-anal Application of NRL001-cream for 14 Days.

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.

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 < 90 mmHg, diastolic blood pressure > 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