Clinical trial NCT03830762: Xanamem™ in Healthy Elderly Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Safety
Peripheral Neuropathy
Cortisol
Central Nervous System
Cognitive Function
Healthy Ageing
Small Fibre Neuropathy
Cerebrospinal Fluid
Electrocardiography
Keywords: Actinogen
Xanamem
UE2343
Cortisol
11β-HSD1
11-beta-Hydroxysteroid Dehydrogenase Type 1
Healthy Ageing
Peripheral Neuropathy
Safety
Dose Escalation
Elderly
XanaHES
emestedastat
Lead sponsor: Actinogen Medical
Sponsor class: INDUSTRY
Collaborators: name: ICON plc
First posted: 2019-02-05
Enrollment: 42
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: OTHER

Brief summary: 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: 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.

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (AEs)
timeFrame: 20 Weeks (Screening up to Week 16 Follow-Up [4 Weeks Post Last Dose of Study Drug ± 4 Days])
measure: Incidence of Clinically Significant Changes in Serum Biomarker Levels in a Standard Serum Chemistry Panel
timeFrame: Screening up to Week 16 (Follow-Up [4 Weeks Post Last Dose of Study Drug ± 4 Days])
measure: Incidence of Clinically Significant Laboratory Haematological Biomarker Levels in a Standard Haematology Panel.
timeFrame: Screening up to Week 16 (Follow-Up [4 Weeks Post Last Dose of Study Drug ± 4 Days])
measure: Incidence of Clinically Significant Changes or Abnormalities Following Physical Examination
timeFrame: 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])
measure: Nerve Conduction Assessments
timeFrame: Screening up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days])
measure: Neuropathy Total Symptom Score-6 (NTSS-6)
timeFrame: Screening, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up) and Telephone Contact (Ad Hoc)
measure: Toronto Clinical Neuropathy Score (TCNS)
timeFrame: Screening, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up) and Telephone Contact (Ad Hoc)
measure: Skin Biopsy
timeFrame: At Baseline and Week 12 (End of Treatment)
measure: Quantitative Sensory Testing (QST)
timeFrame: Screening up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days])
measure: Columbia Suicide Severity Rating Scale (CSSRS)
timeFrame: Screening, Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up)
measure: Electrocardiogram (ECG)
timeFrame: Screening up to Week 16 (Follow-Up Visit [4 Weeks Post Last Dose of Study Drug ± 4 Days])
Secondary outcomes:
Other outcomes:
measure: Detection Test (Cogstate Test Battery)
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up)
measure: Identification Test (Cogstate Test Battery)
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up)
measure: One Back Working Memory Test (Cogstate Test Battery)
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up)
measure: One Card Learning Test (Cogstate Test Battery)
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up)
measure: Continuous Paired Associate Learning Test ([CPAL; Paired Associate Learning] Cogstate Test Battery)
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up)
measure: Pharmacokinetics Blood Sample Assessment
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment), Week 16 (Follow-Up) and Unscheduled Safety Visit throughout duration of study up to Follow-Up Visit (4 Weeks Post Last Dose of Study Drug ± 4 Days)]
measure: Cortisol Concentration
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment) and Week 16 (Follow-Up)
measure: Optional Cerebrospinal Fluid Assessment
timeFrame: Week 12 (End of Treatment)
measure: Health Related Quality of Life: EQ-5D-5L
timeFrame: Baseline, Week 2, Week 4, Week 8, Week 12 (End of Treatment) and Week 16 (Follow-Up)
Locations:
city: Perth
country: Australia
facility: Linear Clinical Research
state: Western Australia
Study officials:
affiliation: Actinogen Medical
name: Bill Ketelbey, MD
role: STUDY_CHAIR
References:
citation: Webster SP, McBride A, Binnie M, Sooy K, Seckl JR, Andrew R, Pallin TD, Hunt HJ, Perrior TR, Ruffles VS, Ketelbey JW, Boyd A, Walker BR. Selection and early clinical evaluation of the brain-penetrant 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor UE2343 (Xanamem). Br J Pharmacol. 2017 Mar;174(5):396-408. doi: 10.1111/bph.13699. Epub 2017 Jan 25.