Study of Escalating Doses of NRL001 Given in Slow-release Rectal Suppositories of Different Weights

A Randomised, Placebo-controlled, Double-blind, Dose Escalation Study in Healthy Volunteers to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Doses of Rectal Suppositories Containing Between 5 and 15 mg NRL001 or Matching Placebo for Two Different Sized Suppositories (1 g and 2 g).

Studies investigating single doses of different NRL001 formulations showed formulation-dependent differences in exposure, even though they had similar effects on mean anal resting pressure (MARP). This study is a first step in investigating the hypothesis that a better balance between desired anal effects and undesired systemic effects can be reached with a NRL001-slow release suppository than with previously studied formulations.

To this purpose, single doses of 5 to 15 mg, administered as 1 g and 2 g suppositories, are being investigated with regard to their pharmacokinetics and systemic effects (blood pressure, pulse rate, electrocardiographic heart rate).

Study Overview

• Status: Completed
• Conditions: Incontinence
• Intervention / Treatment: Drug: NRL001

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Belfast, United Kingdom, BT2 7BA
    • Bio-Kinetic Europe Limited

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy adult male or female volunteers (as determined by medical history, physical examination, laboratory test values, vital signs, and electrocardiograms [ECGs] at screening) aged 18-45 years.
2. Non-smokers from 3 months of receiving first dose and for the duration of the study.
3. Body Mass Index (BMI) ≥ 18 and ≤ 30 kg/m2.
4. Able and willing to receive rectal treatments.
5. Able to voluntarily provide written informed consent to participate in the study.
6. Must understand the purposes and risks of the study and agree to follow the restrictions and schedule of procedures as defined in the protocol.
7. Female volunteers must be postmenopausal (for at least one year and confirmed by serum FSH at screening), surgically sterile, practising true sexual abstinence, or use two highly effective methods of contraception as follows throughout the study until after post study physical: contraceptive implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), vasectomised partner or barrier method (condom or occlusive cap) with spermicidal foam/gel/film/cream/suppository.
8. Hormonal and IUD methods of contraception must be established for a period of 3 months prior to dosing and cannot be changed or altered during the study.
9. Females of child bearing potential must have a negative pregnancy test at screening (β-HCG) and prior to each dosing.
10. Sexually active male volunteers must use condoms with their partners throughout the study and for 90 days after completion of the study in addition to their normal mode of contraception.
11. Male volunteers must not donate sperm during the study and for 90 days after completion of the study.
12. Must be willing to consent to have data entered into The Over Volunteering Prevention System.
13. The volunteer's primary care physician must confirm that there is nothing in their medical history that would preclude their enrolment into this clinical study.

Exclusion Criteria:

1. Positive for HIV, hepatitis B, or hepatitis C as demonstrated by the results of testing at screening.
2. History or presence of any significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal (GI), endocrine, immunologic, dermatologic, neurologic or psychiatric disease.
3. History or presence of aortic stenosis or hypertrophic cardiomyopathy.
4. History or presence of any ano-rectal conditions, clinically significant latex allergy or clinically significant drug allergy.
5. Presence of any ECG abnormalities (during rest or during the exercise stress test).
6. Pregnant or lactating females.
7. Laboratory values at screening which are >1.5x the upper limit of normal for that parameter or <1.5x the lower limit of normal for that parameter, as applicable, or which are abnormal or deemed to be clinically significant according to Bio-Kinetic Europe Ltds SOPs, unless agreed in advance by the Sponsor's Responsible Medical Officer and the Bio-Kinetic Investigator.
8. Current or history of drug or alcohol abuse or a positive drugs of abuse test at screening or check in.
9. Volunteers who, in the opinion of the Investigator, are unsuitable for participation in the study.
10. Participation in a clinical drug study during the 90 days preceding the initial dose in this study.
11. Any significant illness during the screening period preceding entry into this study.
12. Donation of blood or blood products within 90 days prior to study drug administration, or at anytime during the study, except as required by this protocol.
13. Strenuous exercise during study conduct and one week prior to dosing (with the exception of the exercise stress test).
14. Consumption of alcoholic beverages within 24 hours prior to each dosing. Abstinence is required during study confinement.
15. Consumption of xanthine-containing products within 24 hours of each dosing and during study confinement.
16. Use of any disallowed concomitant medication including over-the-counter items within 14 days prior to study drug administration until the end of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose; NRL001 at 5, 7.5, and 10 mg administered in a dose escalating manner with placebo in a random position in the sequence. NRL001 is contained in either a 1 g or a 2 g slow release rectal suppository.	Drug: NRL001; Four single doses of NRL001 or placebo. NRL001 is administered at lower (5, 7.5 and 10 mg) or higher (10, 12.5 and 15 mg) doses in a slow release rectal suppository weighing either 1 g or 2 g.
Experimental: High Dose; NRL001 at 10, 12.5, and 15 mg administered in a dose escalating manner with placebo in a random position in the sequence. NRL001 is contained in either a 1 g or a 2 g slow release rectal suppository.	Drug: NRL001; Four single doses of NRL001 or placebo. NRL001 is administered at lower (5, 7.5 and 10 mg) or higher (10, 12.5 and 15 mg) doses in a slow release rectal suppository weighing either 1 g or 2 g.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics of different strengths of NRL001 rectal suppositories	Up to 36 hours post-dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Dose-related effects on cardiovascular parameters compared with placebo.	Up to 36 hours post-dose
To assess the safety and tolerability of NRL001.	Up to 36 hours post-dose

Collaborators and Investigators

• Sponsor: Norgine
• Investigators: Principal Investigator: David Bell, MRCGP MFPM, BioKinetic Europe Ltd

Publications and helpful links

General Publications

• Bell D, Pediconi C, Jacobs A. Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights. Colorectal Dis. 2014 Mar;16 Suppl 1:16-26. doi: 10.1111/codi.12542.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: February 23, 2009
• First Submitted That Met QC Criteria: February 24, 2009
• First Posted (Estimate): February 25, 2009

Study Record Updates

• Last Update Posted (Estimate): December 23, 2009
• Last Update Submitted That Met QC Criteria: December 21, 2009
• Last Verified: December 1, 2009

More Information

Terms related to this study

• Other Study ID Numbers: NRL001-02/2008 (SUSD)