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Trial registered on ANZCTR


Registration number
ACTRN12620000957998
Ethics application status
Approved
Date submitted
1/07/2020
Date registered
25/09/2020
Date last updated
21/01/2022
Date data sharing statement initially provided
25/09/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1 Study to Evaluate the Safety, Pharmacokinetic (PK) and Effects of CST-2032 in Healthy Volunteers and Subjects with Mild Cognitive Impairment or Parkinson’s Disease
Scientific title
An Open-Label Ascending Single-Dose, and Randomized, Double-blind, Placebo-controlled, Ascending Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CST-2032 in Healthy Volunteers and Subjects with Mild Cognitive Impairment or Parkinson’s Disease
Secondary ID [1] 301650 0
None
Universal Trial Number (UTN)
U1111-1252-9398
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mild Cognitive Impairment 318063 0
Parkinson's disease 318064 0
Condition category
Condition code
Neurological 316098 316098 0 0
Parkinson's disease
Neurological 316099 316099 0 0
Other neurological disorders
Neurological 316100 316100 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase 1 open-label single ascending dose, and randomized, double-blind, placebo-controlled, multiple-ascending dose study to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic effects of oral doses of CST-2032 in healthy adult subjects (Parts A, B and D). In addition, an optional cohort of subjects with MCI or PD may be enrolled to evaluate the effects of a single dose of CST-2032 (Part C).

The starting oral dose of 1 mg CST-2032 (in Cohort A1, Part A) is predicted to deliver a maximum plasma concentration in humans that is below the exposures at which clinical effects were noted in nonclinical studies. The dose of CST-2032 to be administered to subject in all subsequent cohorts will be determined by a Dose Level Review Meeting (DLRM) based on observed safety, PK and pharmacodynamics (where available) from prior cohorts.

CST-2032 will be administered alone or in combination with CST-107 to determine doses of CST-107 that mitigate peripheral effects of CST-2032, e.g. on heart rate, while preserving possible central effects on cerebral perfusion, pupillary light reflex, and cognition. The decision to dose participants in cohorts A7, A8, B5, D2 and D3 with or without CST-107 will be determined by the participating Investigators and study medical monitor based on available safety and PK data. The dose of CST-107 that will be administered to participants in cohorts A7, A8 and B5 will be a dose between 1 and 40 mg. The dose of CST-107 for participants in Cohorts D1-D3 will be defined based on expert review by participating Investigators and study medical monitor of all available safety and PK data from prior cohorts with the aim of identifying the lowest dose of CST-107 that mitigates the peripheral effects of CST-2032 (e.g. on heart rate). The mode of administration of CST-107 is an oral capsule or tablet.

A subject can be enrolled into only one cohort.

Cohorts in Part A will be enrolled sequentially, and safety data up to Day 3 must be reviewed by the DLRM prior to enrolling the next planned cohort (a minimum of 3 days between each cohort).

Enrollment into Parts B and C may not commence until after the DLRM has reviewed data from Cohort A3 in Part A. Cohorts in Part B will also be enrolled sequentially, and safety data up to Day 4 must be reviewed by the DLRM prior to enrolling the next planned Part B cohort (a minimum of 4 days between each cohort).

Enrollment of Part C is optional and will be determined in the DLRM based on emerging safety, tolerability, PK and pharmacodynamic data (as available) from Part A.

Enrollment into Part D may not commence until after the DLRM has reviewed repeat-dose data from the first cohort in Part B.

Interventions in the study include the following:

In Part A, up to 8 healthy subjects will be enrolled in each of the following cohorts:
- Cohort A1 – single oral dose of 1 mg CST-2032
- Cohort A2 – single oral dose of approximately 3 mg CST-2032
- Cohort A3 – single oral dose of approximately 10 mg CST-2032
- Cohort A4 – single oral dose of approximately 30 mg CST-2032
- Cohort A5 – single oral dose of CST-2032 to be determined
- Cohort – Food Effect – single oral dose up to 30 mg CST-2032 to be administered with and without food, 7 days apart
- Optional Cohort A7 - single oral dose of CST-2032 with or without oral dose of CST-107 (doses to be determined by the DLRM)
- Optional Cohort A8 - single oral dose of CST-2032 with or without oral dose of CST-107 (doses to be determined by the DLRM)

In Part B - 8 healthy subjects to be enrolled in each cohort. In the first cohort of Part B, the dose of CST-2032 will be determined at the DLRM based on the safety, PK and pharmacodynamic data from prior cohorts in Part A. The starting dose in Part B will not exceed the maximum dose evaluated in Part A or the maximum dose tolerated in Part A. In all subsequent cohorts in Part B, the dose of CST-2032 will be determined at the DLRM based on safety, PK and pharmacodynamic data from prior cohorts in Parts A and B. At no time in the study will the DLRM select a dose of CST-2032 that exceeds the maximum tolerated dose observed in humans, or that is predicted to give rise to human exposures above the established no-observed-adverse-effect level in completed toxicity studies with CST-2032.
- Cohort B1 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days
- Cohort B2 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days
- Cohort B3 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days
- Cohort B4 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days
- Optional Cohort B5 - once-daily oral dose of CST-2032 with or without oral dose of CST-107 (doses to be determined by the DLRM) for 7 days

In Part C - up to 8 subjects with MCI or PD to be enrolled:
- Cohort C1 – single oral dose of CST-2032. The dose of CST-2032 will be determined at the DLRM based on safety, PK and pharmacodynamic data from prior cohorts in Parts A, B and D. At no time in the study will the DLRM select a dose of CST-2032 that exceeds the maximum tolerated dose observed in humans, or that is predicted to give rise to human exposures above the established no-observed-adverse-effect level in completed toxicity studies with CST-2032.

In Part D, healthy subjects will undertake within-subject dose titration of CST-2032 and/or CST-107 in order to explore doses/dose combinations that mitigate peripheral effects of CST-2032, e.g. on heart rate, while preserving possible central effects on cerebral perfusion and pupillary light reflex. Up to 8 healthy subjects will be enrolled in each of the following cohorts:
- Cohort D1, open-label CST-2032 at one or more dose levels (up to the protocol-defined maximum dose levels) once-daily from Day 1 through Day 7 with oral dose of CST-107 (up to 40 mg) pre-administered or co-administered on one or more of the dosing days.
- Cohort D2, open label CST-2032 from Day 1 through Day 3 and open-label CST-107 on one or more of those dosing days. CST-2032 will be administered as escalating doses on Day 1, Day 2 and Day 3 at doses of CST-2032 (up to the maximum protocol-defined dose levels) selected by the DLRM with or without pre-administered or co-administered CST-107 (up to 40 mg) on one or more of the dosing days.
- Optional Cohort D3, open label CST-2032 from Day 1 through Day 3 and open-label CST-107 on one or more of those dosing days. CST-2032 will be administered as escalating doses on Day 1, Day 2 and Day 3 at doses of CST-2032 (up to the maximum protocol-defined dose levels) selected by the DLRM with or without pre-administered or co-administered CST-107 (up to 40 mg) on one or more of the dosing days.

CST-2032 is an oral solution and will be administered at the clinic in the morning by the research nurse; mouth check will be performed to monitor adherence.
Intervention code [1] 317955 0
Treatment: Drugs
Comparator / control treatment
Placebo (in Part B only) is an oral solution made from a commercially manufactured vehicle formulation that contains purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, and flavoring, and is buffered with citric acid and sodium citrate.
Control group
Placebo

Outcomes
Primary outcome [1] 324293 0
Adverse events (AE) assessed as a composite of electrocardiograms (ECGs), vital signs, laboratory safety tests (hematology, chemistry and urinalysis) in healthy participants and in patients with Mild Cognitive Impairment (MCI) or Parkinson's disease (PD).

CST-2032 has never been dosed in humans, so its effects on humans are not known. However, based on observations from nonclinical studies and other approved drugs with similar mechanisms of action, the following adverse events may arise: increased heart rate, decreased blood pressure, high sugar in the blood, palpitations (feelings that your heart is skipping a beat, fluttering, pounding, or racing), headache.
Timepoint [1] 324293 0
Adverse events, vital signs (including heart rate and blood pressure) and ECGs will be measured at least once-daily in all 4 parts of the study while the subject is resident in clinic, and at the end-of-study visit:
Days 1 through Day 8 in Part A
Days 1 through Day 5 and Days 8 through Day 12 in Part A - Food Effect
Days 1 through Day 15 in Parts B and D
Days 1 through Day 8 in Part C

In addition, safety labs (chemistry, hematology, urinalysis) will be run every 1-3 days in those intervals.
Secondary outcome [1] 384263 0
CST-2032 and CST-107 drug levels in plasma
Timepoint [1] 384263 0
Blood samples for assessment of CST-2032 PK will be collected at least once-daily in all 4 parts of the study while the subject is resident in clinic, and at the end-of-study visit.

In Part A, PK samples will be collected at the following times: within 1 hour prior to dosing CST-107 (if administered), within 0.5 hour prior to dosing CST-2032 and post-dose at hour 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, (Day 1); 24, 30, 36 (Day 2); 48,, 60 (Day 3); 72 (Day 4); 96 (Day 5); and at any time during the EOS visit.

In Part A - Food Effect, PK samples will be collected within 1 hour prior to dosing and post-dose at hour 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, (Day 1 and Day 8); 24, 30, 36 (Day 2 and Day 9); 48, 60 (Day 3 and Day 10); 72 (Day 4 and Day 11). 96 (Day 5 and Day 12), and at any time during the visit on Day 15 (EOS) visit

In Part B, PK samples will be collected:
• On Days 1 and 7 within 1 hour prior to dosing CST-107 (if administered), within 0.5 hour prior to dosing CST-2032 and post-dose at hour 0.25, 0.5, 2, 4, 6, 8, 12;
• On Days 2 – 6 within 0.5 hour prior to dosing of study drug;
• On Day 8: at 24, and 36 hours after the last dose of study drug;
• On Day 9 at 48 and 60 hours after the last dose of study drug;
• On Day 10 prior to discharge from the clinic.

In Part C, PK samples will be collected at the following times:
• Day 1: within 2 hour prior to dosing CST-107 (if administered), within 0.5 hour prior to dosing CST-2032 and after administration of CST-2032 at hour o.25, 0.5, 1, 2, 3, 4, 6, 9,
• Day 2: 24, 30,
• Day 3: 48, and
• Day 8 (EOS): at any time.

In Part D Cohort D1, PK samples will be collected:
• On Day 1 through Day 7 within 1 hour prior to dosing of CST-107 (if administered), within 0.5 hour prior to dosing of CST-2032 and at 0.25, 0.5, 1, 2, 4, 6, 12 hours after dosing of CST-2032
• On Day 8: at 24 and 36 hours after the last dose of CST-2032;
• On Day 9 at 48 hours after the last dose of CST-2032.

In Part D Cohorts D2 and D3, PK samples will be collected:
• On Days 1, 2, and 3 within 1 hour prior to dosing of CST-107 (if administered), within 0.5 hour prior to dosing of CST-2032 and at 1, 2, 4, 6 hours after dosing of CST-2032;
• On Day 4: at 24 and 30 hours after administration of CST-2032 on Day 3.

PK parameters will include the area under the drug concentration-time curve (AUC), Tmax, maximum concentration (Cmax), time to lower plasma drug concentration by 50% (T1/2) and Time of maximum concentration (Tmax).
Secondary outcome [2] 384264 0
Change in cerebral perfusion as measured by non-invasive arterial spin labeling magnetic resonance imaging (MRI), after CST-2032 treatment in healthy participants and patients with MCI or PD.
Timepoint [2] 384264 0
Day 1 in Part A and Part C
Days 1 and 5 in Part B
Secondary outcome [3] 384273 0
CST-2032 and CST-107 levels in urine
Timepoint [3] 384273 0
Day 7 for Part B only.
Secondary outcome [4] 405269 0
CST-2032 and CST-107 levels in cerebrospinal fluid
Timepoint [4] 405269 0
Days 2 and 6 in Cohort D1 only
Secondary outcome [5] 405270 0
Effects of study drugs on cognition using the Cambridge Neuropsychological test automated battery [CANTAB]
Timepoint [5] 405270 0
Day 1 in Cohort C1
Days 1, 2, and 3 in Cohorts D2 and D3

Eligibility
Key inclusion criteria
Healthy participants must meet the following:
- Male or female aged 18-50 years or 55-75 in Cohorts D2 and D3
- Women of child-bearing potential must agree to effective methods of birth control
- Free from clinical significantly illness or disease
- No current use of any prescription medications, over-the-counter medications or nutritional supplements.

MCI patients must meet the following:
- Male or female aged 45-75 years
- Women of child-bearing potential must agree to effective methods of birth control
- Meet the criteria for amnestic MCI, as per the National Institute on Aging-Alzheimer's Association core clinical criteria
- A score of greater than or equal to one standard deviation below age and educational norms in the Digit Symbol Substitution Test (DSST)

PD patients must meet the following:
- Male or female aged 45-75 years
- Women of child-bearing potential must agree to effective methods of birth control
- Meet the criteria for PD defined by the cardinal sign, bradykinesia, plus the presence of at least 1 of the following: resting tremor, rigidity, or impairment of postural reflexes, and without any other known or suspected cause of Parkinsonism
- Mini-Mental Status Exam (MMSE) Score greater than or equal to 26
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All participants must not meet the following:
- Women who are pregnant or lactating
- History of any clinically significant disease or illness
- Clinically significant laboratory or ECG abnormality.
- Positive screening test for human immunodeficiency virus (HIV).
- Positive screening test for hepatitis C antibody (HCV Ab) or current hepatitis B infection.
- Positive screening test for SARs-CoV2 or, if tests are not available, evidence of possible ongoing infection based on body temperature, blood oxygen and Investigator judgment.
- History of drug or alcohol abuse >12 months prior to Screening.
- History of nicotine use >6 months.
- A positive test for drugs of abuse or alcohol
- Contraindications for MRI scans.

Other exclusion criteria apply, such as: specific exclusions for background medications, concurrent illness in each of the eligible participant groups (healthy subjects, or subjects with MCI or PD).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Part A: open-label
Part B: randomized 6:2 to CST-2032:placebo.
Part C: open-label.
Part D: open-label

In Part B, study drug assignment will be determined by a computer-generated random sequence. All participants and investigators will be blinded to study drug assignment (CST-2032 or placebo). Unblinded personnel, include the site pharmacist, the biostatistician and/or designee conducting bioanalyses or statistical analyses for PK, and the Sponsor, all of whom will have no involvement in safety assessments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Sequential cohort enrollment with increasing doses of CST-2032 administered as a single dose, or multiple repeat doses over 1 week.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
No formal sample size estimation was performed; the sample size is based on practical considerations and is standard for these types of studies.

Statistical summaries will be descriptive in nature (e.g., means, standard deviations, and percentiles). All subjects will be grouped according to treatment actually received and by cohort.

Safety outcomes will be listed and summarized descriptively by treatment arm, as applicable. All reported adverse events will be coded to system organ class (SOC) and preferred term (PT), using MedDRA®.

Laboratory data will be tabulated and listed, and values outside of normal ranges identified.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
CuraSen decided to end this study for business reasons only, and there are no safety concerns with the program.
Date of first participant enrolment
Anticipated
Actual
26/08/2020
Date of last participant enrolment
Anticipated
Actual
24/09/2021
Date of last data collection
Anticipated
Actual
1/10/2021
Sample size
Target
118
Accrual to date
Final
79
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment outside Australia
Country [1] 22702 0
New Zealand
State/province [1] 22702 0
Canterbury
Country [2] 22703 0
Belgium
State/province [2] 22703 0
Leuven

Funding & Sponsors
Funding source category [1] 306083 0
Commercial sector/Industry
Name [1] 306083 0
CuraSen Therapeutics, Inc.
Country [1] 306083 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
CuraSen Therapeutics, Inc.
Address
930 Brittan Avenue, #306
San Carlos, CA 94070, USA
Country
United States of America
Secondary sponsor category [1] 306548 0
Commercial sector/Industry
Name [1] 306548 0
Illingworth Research Group Limited
Address [1] 306548 0
Hazelwood House
Lakewood Way
Tytherington Business Park
Macclesfield
SK10 2XR
United Kingdom
Country [1] 306548 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306304 0
Health and Disability Ethics Committees
Ethics committee address [1] 306304 0
133 Molesworth Street
Thorndon Wellington 6011
Ethics committee country [1] 306304 0
New Zealand
Date submitted for ethics approval [1] 306304 0
24/06/2020
Approval date [1] 306304 0
28/07/2020
Ethics approval number [1] 306304 0

Summary
Brief summary
This is an open-label single ascending dose (SAD), and randomized, double-blind, placebo-controlled, multiple-ascending dose (MAD) study to evaluate the safety, PK and pharmacodynamic effects of oral doses of CST-2032 in healthy adult participants. In addition, an optional cohort of patients with Mild Cognitive Impairment (MCI) or Parkinson’s disease may be enrolled to evaluate the effects of a single dose of CST-2032. The study will additionally evaluate whether peripheral effects that may emerge with CST-2032 can be inhibited by CST-107.

Up to 17 cohorts are planned for this study, with approximately 4-8 subjects per cohort following confirmation of study eligibility during the screening period.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103434 0
Dr Chris Wynn
Address 103434 0
New Zealand Clinical Research
Level 4, 265 Antigua Street,
Christchurch 8011
Country 103434 0
New Zealand
Phone 103434 0
+64 3 3729477
Fax 103434 0
Email 103434 0
[email protected]
Contact person for public queries
Name 103435 0
Chris Wynn
Address 103435 0
New Zealand Clinical Research
Level 4, 265 Antigua Street,
Christchurch 8011
Country 103435 0
New Zealand
Phone 103435 0
+64 3 3729477
Fax 103435 0
Email 103435 0
[email protected]
Contact person for scientific queries
Name 103436 0
Chris Wynn
Address 103436 0
New Zealand Clinical Research
Level 4, 265 Antigua Street,
Christchurch 8011
Country 103436 0
New Zealand
Phone 103436 0
+64 3 3729477
Fax 103436 0
Email 103436 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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