Xanamem™ in Healthy Elderly Subjects

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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XanaHES: A Phase I, Single Blinded, Central Reader Blinded, Placebo-Controlled, Dose Escalation Study of Xanamem™ to Assess Safety and Tolerability in Healthy Elderly Subjects

Conditions
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Safety, Peripheral Neuropathy, Cortisol, Central Nervous System, Cognitive Function, Healthy Ageing, Small Fibre Neuropathy, Cerebrospinal Fluid, Electrocardiography

Intervention / Treatment
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* Drug: Xanamem
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteers aged 50 to 75 years. Female subjects: 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. Women of childbearing potential (WOCBP) must have a negative pregnancy test. Male Subjects: 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 Who are permanently sterile or have had bilateral orchiectomy or bilateral vasectomy. No disease which may cause a peripheral neuropathy. 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). 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: Clinically significant abnormalities in vital signs (blood pressure, heart rate, respiration rate and oral temperature), as determined by the investigator. Body Mass Index (BMI) > 38 kg/m2 Clinically significant abnormal haematology, biochemistry and urine examination values, as determined by the investigator. Participants who have a history of liver disease, including fatty liver, or LFT elevations requiring investigation will not be eligible. Has had a significant systemic illness or infection within the past 4 weeks prior to randomisation, as determined by the investigator. Documented diagnosis of Type I or Type II diabetes. 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. Has any uncontrolled clinical condition relating to glucose or lipid metabolism. Subjects with clinical evidence of peripheral neuropathy or historical evidence of clinically significant nerve conduction abnormalities. Clinical evidence of neuropathy. Clinically significant electrocardiogram (ECG) abnormalities, including QTc interval > 450 msec (male) and > 470 msec (female), following ECG tracings at Screening. Use of any prohibited medication. Participation in another clinical study of a drug or device whereby the last investigational drug/device administration is within 60 days of Screening. 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). 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A Dose Escalation Committee will review the results from Cohort 1 (20 mg active vs. placebo arms) and provide a recommendation to proceed with Cohort 2 (30 mg active vs. placebo arms) randomisation which involves a dose escalation.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 / Cohort 2 (Active)<br>20mg or 30mg capsules of Xanamem respectively, to be administered PO once daily. | Drug: Xanamem<br>* Oral Xanamem capsules 20mg or 30mg, administered PO once daily. Xanamem is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343.<br>* Other names: UE2343;|
| Placebo Comparator: Cohort 1 / Cohort 2 (Placebo)<br>Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily. | Drug: Matching Placebo<br>* Matching placebo which is identical in appearance to the test product (20mg, 30mg Xanamem™ QD) except that it contains no active ingredient.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (AEs) | The number, type, and severity of treatment-emergent adverse events (AEs) that are reported from Screening Visit to Follow-up Visit will be collected and evaluated. | 20 Weeks (Screening up to Week 16 Follow-Up [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 
| Incidence of Clinically Significant Changes in Serum Biomarker Levels in a Standard Serum Chemistry Panel | Collection of blood samples for clinical laboratory testing to assess any clinically significant changes in standard serum chemistry measures. | Screening up to Week 16 (Follow-Up [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 
| Incidence of Clinically Significant Laboratory Haematological Biomarker Levels in a Standard Haematology Panel. | Collection of blood samples for clinical laboratory testing to assess any clinically significant changes in standard haematology measures. | Screening up to Week 16 (Follow-Up [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 
| Incidence of Clinically Significant Changes or Abnormalities Following Physical Examination | Evaluation of any clinically significant changes or abnormalities reported following a standard Physical Examination. | Screening up to Week 16 (Follow-Up) and Unscheduled Safety Visit throughout duration of study up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 
| Nerve Conduction Assessments | Nerve Conduction assessments will be used to detect presence and severity of nerve damage. | Screening up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 
| Neuropathy Total Symptom Score-6 (NTSS-6) | Changes in the Neuropathy Total Symptom Score (NTSS-6) administered by a physician to assess a subjects' medical history. Each item will also be graded for its frequency and intensity, adding up to a total score from 0 to 21.96 points. A total score of > 6 would exclude the subject from the study. | Screening, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up) and Telephone Contact (Ad Hoc) | 
| Toronto Clinical Neuropathy Score (TCNS) | Changes in Toronto Clinical Neuropathy Score (TCNS) to detect for neuropathy out of a total score of 19; scales are defined as follows: 0-5 = no neuropathy; 6-8 = mild neuropathy; 9-11 = moderate neuropathy; ≥ 12 = severe neuropathy. | Screening, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up) and Telephone Contact (Ad Hoc) | 
| Skin Biopsy | A 3mm skin sample will be taken via skin punch biopsy to detect intra-epidermal nerve fiber density; this allows for the objectification and quantification of a small-fiber neuropathy. | At Baseline and Week 12 (End of Treatment) | 
| Quantitative Sensory Testing (QST) | Thermal sensory testing using Quantitative Sensory Testing (QST) for cold, warm and heat pain to detect peripheral nerve disorders. | Screening up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 
| Columbia Suicide Severity Rating Scale (CSSRS) | Any change in Columbia Suicide Severity Rating Scale (CSSRS) will assess suicidal ideation and behaviour. Suicidal ideation score: Any score greater than 0 is important and may indicate the need for mental health intervention. Suicidal ideation intensity rating: The five intensity item scores create a total score (range 0 to 25) to represent the intensity rating, if the patient did not endorse any suicidal ideation the intensity rating is 0. | Screening, Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up) | 
| Electrocardiogram (ECG) | Any clinically significant electrocardiogram (ECG) abnormalities will be recorded, including corrected QT interval (QTc) of > 500 msec. | Screening up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Actinogen, Xanamem, UE2343, Cortisol, 11β-HSD1, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Healthy Ageing, Peripheral Neuropathy, Safety, Dose Escalation, Elderly, XanaHES