Study to Investigate Safety and Response to 1 or 2 g Rectal Suppositories Containing 5 or 10 mg NRL001.

Study Overview
=================
Brief Summary
-----------------
This is a healthy volunteer three-way crossover study. A total of 12 subjects will receive three single administrations of 1 g rectal suppositories (containing either 5 mg NRL001, 10 mg NRL001 or matching placebo), with a washout period of at least 7 days between dosings. A further 12 subjects will receive three single administrations of 2 g rectal suppositories (containing either 5 mg NRL001, 10 mg NRL001 or matching placebo), again with a 7 day washout period between dosings. The pharmacodynamic response, pharmacokinetics and safety profile will be determined.

Official Title
-----------------
Randomised, Double-blind, Single Dose, Three-way, Cross-over Study to Investigate the Safety and Response to 1g or 2g Rectal Suppositories Containing 5 mg or 10 mg 1R,2S-methoxamine Hydrochloride [NRL001] or Matching Placebo

Conditions
-----------------
Fecal Incontinence

Intervention / Treatment
-----------------
* Drug: NRL001
* Drug: NRL001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: No previous history of ano-rectal conditions or diseases No history of cardiovascular disease 18 to 60 years of age Males and females (pre-menopausal females of child-bearing potential must be using adequate contraceptive methods and have a negative pregnancy test before the start of the study) Exclusion Criteria: Use of medication in the last 30 days with a vasodilatory activity, or use of any medication currently or within the last 30 days which the Investigator believes may affect the study participation or results Use of monoamine oxidase inhibitors presently or within the last 2 weeks before study participation Use of any medication in the last 30 days applied to the anus and/or via the rectum Application of any unlicensed medication within the previous 3 months or participation in any other research study in the last three months which involved being paid a disturbance allowance; having an invasive procedure (e.g. venepuncture >50ml, endoscopy) or exposure to ionising radiation. Regular intake of more than 21 units of alcohol per week History or any evidence of cardiovascular disease including ischaemic heart disease and hypertension (defined on examination: systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 90 mmHg; based on at least two separate readings), peripheral vascular disease or Raynaud's syndrome Presence of diabetes mellitus History or symptoms of thyroid diseases, including hypo- or hyperthyroidism Pregnant or lactating females History of any clinically relevant allergy Presence of concomitant gastrointestinal diseases or disorders, such as significant abdominal symptoms and haemorrhoids but also any significant organ (e.g. renal, hepatic or cardiac) dysfunction Volunteers whom the Investigator feels would not comply with the requirements of the trial Volunteers who have been exposed to more than 5 mSv of ionising radiation in the last 12 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 g suppository<br>Subjects receive 5 mg NRL001, 10 mg NRL001 and placebo in a 1g rectal suppository | Drug: NRL001<br>* Subjects receive single doses of 5 mg NRL001, 10 mg NRL001 and placebo in a 1 g rectal suppository, with a 7-day washout period between dosing.<br>|
| Experimental: 2 g suppository<br>Subjects receive 5 mg NRL001, 10 mg NRL001 and placebo in a 2 g rectal suppository. | Drug: NRL001<br>* Subjects receive single doses of 5 mg NRL001, 10 mg NRL001 and placebo in a 2 g rectal suppository, with a 7-day washout period between dosing.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MARP after a single dose |  | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic plasma assessment to determine systemic uptake |  | 6 hours | 
| Adverse events |  | 6 hours | 
| Cardiovascular parameters; heart rate and blood pressure |  | 6 hours |