Xanamem™ in Healthy Elderly Subjects

Xanamem™ is being developed as a potential drug for Alzheimer's disease. This study drug has been designed to change the cortisol levels in the brain. Cortisol is a naturally occurring hormone in the body. It is believed that reducing the level of cortisol will be a benefit in the treatment of Alzheimer's disease.

The XanaHES study is testing the safety and tolerability of Xanamem. It is planned to enrol approximately 84 participants, male and female aged from 50 to 75 who are in good health, in the study at 1 centre in Australia.

The XanaHES Phase I study is a single-blind study. Subjects will be randomised to receive either 20mg once daily Xanamem or Placebo in cohort 1. Once all subjects have completed the study treatment of 12 weeks, a dose escalation committee will decide if a new cohort, cohort 2, with 30mg once daily vs placebo is started.

This is a Phase I, randomised, single-centre, single-blind, placebo-controlled study to assess the safety, tolerability of oral Xanamem once daily in healthy elderly subjects.

It is planned to randomise approximately 84 subjects, 42 in each cohort, at a single site in Australia.

Cohort 1 starts with a 20mg QD dose vs matching placebo. A Dose Escalation Committee will review the results from cohort 1 and provide a recommendation to proceed with Cohort 2 randomisation which involves a dose escalation to 30mg.

At the Baseline visit (Week 0), eligible subjects will be randomised on a 30:12 ratio to receive either Xanamem administered orally QD (treatment group) or matching placebo (placebo group). Subjects will return to the study site for visits at Week 2, Week 4, Week 6, Week 8, Week 10, End of Treatment (Week 12) and Follow-up (4 weeks post last dose of study drug) visits, at which study assessments will be performed.

Ad hoc telephone contact may also occur at any other time-point throughout the study, if deemed necessary by the investigator/study nurse, or if the subject wishes to report an adverse event (AE).

Subjects will be interviewed and examined at the study site at each visit and will complete a variety of questionnaires, routine safety evaluations and nerve function tests.

A central reader will review every Nerve Function Monitoring (NFM) assessment performed for each subject for Potential Nerve Safety Signals (PNSS).

Optional cerebrospinal fluid (CSF) sampling will be performed at baseline and end of treatment visits for a small subgroup of subjects, who provide additional consent. Subjects who do not provide consent for this optional sub-study will still be eligible for the main study.

The overall study duration for an individual subject will be 17 to 20 weeks, including a screening period of up to 4 weeks, a single-blind treatment period of 12 weeks, and a follow-up period of 4 weeks. The total duration of the study is expected to be 1.5 years.

Eligibility Criteria:
Inclusion Criteria:

1. Volunteers aged 50 to 75 years.
2. Female subjects:

   1. Post-menopausal women, defined as no menses for 12 months without an alternative medical cause. If there is any concern about the menopausal status of a prospective female subject, a follicle stimulating hormone test (FSH) should be requested to confirm post-menopausal status. Post-menopausal women confirmed by FSH level \> 40 mIU/mL, will be confirmed by the local laboratory.
   2. Women of childbearing potential (WOCBP) must have a negative pregnancy test.
3. Male Subjects:

   1. Who are sexually active, fertile men must use highly effective methods of contraception from Day 1 until 3 months after last dose of study drug if their partners are WOCBP
   2. Who are permanently sterile or have had bilateral orchiectomy or bilateral vasectomy.
4. No disease which may cause a peripheral neuropathy.
5. No evidence of alcohol abuse (defined as greater than 21 standard units per week for males and greater than 14 standard units per week for females).
6. Must provide written informed consent to participate in the study and be willing and able to participate for the maximum of 12 weeks of treatment and 16 weeks of site visits.

Exclusion Criteria:

1. Clinically significant abnormalities in vital signs (blood pressure, heart rate, respiration rate and oral temperature), as determined by the investigator.
2. Body Mass Index (BMI) \> 38 kg/m2
3. Clinically significant abnormal haematology, biochemistry and urine examination values, as determined by the investigator.
4. Participants who have a history of liver disease, including fatty liver, or LFT elevations requiring investigation will not be eligible.
5. Has had a significant systemic illness or infection within the past 4 weeks prior to randomisation, as determined by the investigator.
6. Documented diagnosis of Type I or Type II diabetes.
7. Has a history of disease directly related to the hypothalamus, the pituitary and/or the adrenal glands which affects the hypothalamic-pituitary-adrenal axis function.
8. Has any uncontrolled clinical condition relating to glucose or lipid metabolism.
9. Subjects with clinical evidence of peripheral neuropathy or historical evidence of clinically significant nerve conduction abnormalities. Clinical evidence of neuropathy.
10. Clinically significant electrocardiogram (ECG) abnormalities, including QTc interval \> 450 msec (male) and \> 470 msec (female), following ECG tracings at Screening.
11. Use of any prohibited medication.
12. Participation in another clinical study of a drug or device whereby the last investigational drug/device administration is within 60 days of Screening.
13. Inability to communicate well with the investigator (i.e. language problem, non-fluent English \[as questionnaires and study drug label will be provided in English only\], poor mental development or impaired cerebral function).
14. Subject will undergo the Columbia Suicide Severity Rating Scale (CSSRS), Toronto Clinical Neuropathy Score (TCNS), EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D-5L), and Cogstate Test Battery at the indicated time-points to avoid uncontrolled learning effects. Subjects who need to perform these tests externally to and in parallel with this study will be excluded.
15. For subjects that consent, and are subsequently accepted for enrolled into, the CSF optional sub-study, subjects must have no contraindications to the lumbar puncture procedure as assessed by the Principal Investigator. Such contraindications may include uncontrolled bleeding abnormalities or skin or spine abnormalities.
16. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV). Subjects returning a positive result will be managed by the site in line with standard care.