Safety, Tolerability, Pharmacodynamic and Pharmacokinetics of a Single Rectal Application of 10 mg NRL001 in Elderly Subjects

A Double-blind, Randomised, Placebo-controlled Study in Elderly Subjects to Evaluate the Safety, Tolerability, Pharmacodynamic Effects and Pharmacokinetics of a Single Rectal Application of 10 mg NRL001 in a 2 g Suppository

A total of 26 healthy elderly male and female subjects will receive both 10 mg NRL001 in a 2 g rectal suppository and placebo in this double-blind, cross-over study. The order of treatment will be randomised, with a minimum washout period of 3 days between doses. An end of study assessment will be conducted at least 7 days after administration of the last treatment.

The pharmacokinetics of NRL001 will be determined prior to, and after, dosing. Pharmacodynamics will be examined using a three lead Holter monitor during both treatment periods. Adverse Events, vital signs, ECGs and clinical laboratory parameters will be collected, tabulated, reviewed and recorded throughout the study.

Inclusion Criteria:

Volunteers will be included in the study if they satisfy the following criteria:

• Healthy adult male or female volunteers (as determined by medical history, physical examination, laboratory test values, vital signs and electrocardiograms [ECGs] at screening) aged ≥65 years.
• Non-smokers from 3 months before receiving the first dose and for the duration of the study.
• Body mass index (BMI) ≥ 18 and ≤ 32 kg/m2.
• Able and willing to receive rectal treatments.
• Able to voluntarily provide written informed consent to participate in the study.
• 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 partner's normal mode of contraception.
• Male volunteers must not donate sperm during the study and for 90 days after completion of the study.
• Must understand the purposes and risks of the study and agree to follow the restrictions and schedule of procedures as defined in the protocol.
• Female volunteers must be postmenopausal (for at least 1 year, confirmed by FSH testing at screening).
• Must be willing to consent to have data entered into The Over Volunteering Prevention System (TOPS).
• 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:

Volunteers will be excluded if they fulfil any of the following criteria:

• Positive for HIV, hepatitis B, or hepatitis C as demonstrated by the results of testing at screening.
• History or presence of any significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal (GI), endocrine or immunologic disease.
• History or presence of any clinically significant ano-rectal conditions as judged by the Investigator (e.g. concomitant enlarged symptomatic haemorrhoids or acute presence of anal fissures) or clinically significant drug allergy.
• Blood pressure in excess of 150/90 mmHg or pulse rate below 50 beats per minute at screening.
• Any significant illness during the screening period preceding entry into this study.
• Clinically relevant ECG-abnormalities (e.g. QTc prolongation, acute arrhythmia) during the screening assessment
• Laboratory values which are abnormal and deemed to be clinically significant according to Bio-Kinetic Europe Ltd. SOPs, unless agreed in advance by the Sponsor's Responsible Medical Officer and the Bio-Kinetic Investigator.
• Current or history of drug or alcohol abuse or a positive drugs of abuse test at screening or check in.
• 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.
• Use of any medication applied via the rectum, within 30 days prior to dosing
• Use of any medication currently or within 30 days prior to dosing which the Investigator believes may affect the study participation or results.
• Participation in a clinical drug study during the 90 days preceding the initial dose in this study.
• 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.
• History of any allergy to medication, particularly nifedipine, α adrenoceptor antagonists or latex
• Consumption of alcoholic beverages within 24 hours prior to each dosing period. Abstinence is required during study confinement.
• Consumption of xanthine-containing products within 24 hours of each dosing period and during study confinement.
• Subjects who are considered not competent to consent to the trial or fail a Mini Mental State Exam (MMSE).
• Volunteers who, in the opinion of the Investigator, are unsuitable for participation in the study.