A Study of Clenbuterol (CST-103) Co-administered With Nadolol (CST-107) in Subjects With Neurodegenerative Disorders (CLIN-011)

A Phase II, Randomized, Placebo-Controlled, Double-Blind, Crossover, Study of the Pharmacodynamic Effects of CST-103 Co-administered With CST-107 on the Central Nervous System in Subjects With Neurodegenerative Disorders

This is a Phase II, randomized, placebo-controlled, double-blind, crossover study on the CNS and pharmacodynamic effects of clenbuterol (CST-103) co-administered with nadolol (CST-107) in 4 subject populations with Neurodegenerative Disorders.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment, Lewy Body Dementia, Parkinson's Disease Rapid Eye Movement Sleep Behavior Disorder, Parkinson's Disease Dementia
• Intervention / Treatment: Drug: clenbuterol (CST-103), nadolol (CST-107), matching placebo

Detailed Description

Approximately 40 subjects with Parkinson's Disease (PD) with REM Sleep Behavior Disorder (RBD) and Depressive Symptoms, Mild Cognitive Impairment (MCI) with Depressive Symptoms, Dementia with Lewy Bodies (DLB) with Cognitive Fluctuations, and Parkinson's Disease Dementia (PDD) with Cognitive Fluctuations were to be enrolled in a 2 period, 2-way crossover design following study eligibility confirmation during the screening period. The number of subjects enrolled in each cohort could change as emerging data are reviewed from this and other studies.

During each treatment period, subjects received daily doses of clenbuterol (CST-103) co-administered with nadolol (CST-107) or matching placebo for 14 days. Each treatment period was separated by a washout period of 14 days (+5-day window).

All subjects completed clinical and pharmacodynamic assessments during each treatment period and PK blood samples were collected prior to, during and after study medication administration.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2006
      • The University of Sydney
  • Queensland
    • Brisbane, Queensland, Australia, QLD 4066
      • Wesley Medical Research Ltd
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• New Zealand
  • Christchurch, New Zealand, 8011
    • NZBRI
• United Kingdom
  • Manchester, United Kingdom, M13 9NQ
    • MAC
  • Barnsley
    • Tankersley, Barnsley, United Kingdom, S75 3DL
      • MAC
  • Lancashire
    • Blackpool, Lancashire, United Kingdom, FY2 0JH
      • MAC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Subjects with PD:

• Male or female subjects ≥ 40 and ≤ 80 years of age, at time of informed consent.
• Diagnosed with Parkinson's Disease, as defined by the United Kingdom Parkinson Disease Brain Bank criteria, associated with REM sleep behavior disorder (PD)
• Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during "On" period as documented in the 3 months prior to Screening or completed at Screening.
• Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 28.

Subjects with MCI:

• Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.
• Meet the criteria for amnestic Mild Cognitive Impairment (MCI) as per the National Institute on Aging-Alzheimer's Association core clinical criteria.
• Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26.
• No dementia according to the International Classifications of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV.
• Memory complaint reported by the subject or his/her partner, family member or caregiver.
• Score of greater than or equal to one standard deviation below age and educational norms in the Digit Symbol Substitution Test (DSST) during Screening.
• Cognitive decline not primarily caused by vascular, traumatic, or medical problems.

Subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD):

• Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.
• Diagnosis of dementia associated with Dementia with Lewy Bodies or Parkinson's disease (PDD).
• Documented cognitive fluctuations endorsed on the Dementia Cognitive Fluctuation Scale (DCFS) with a combined score of ≥8 in items 4, 11, 12 and 14.
• Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26.
• Have informant or caregiver throughout the study who will submit written consent to cooperate with this study, who routinely accompanies and/or stays with subject 12 hours or more a week, assists with treatment compliance, provides assessments and is able to escort the subject on required visits to study institution.
• Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during "On" period as documented in the 3 months prior to Screening or completed at Screening.
• Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI.

For ALL Subjects:

• Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males must agree to use a male condom from Day 1 throughout the study when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.
• Females of childbearing potential (i.e., not postmenopausal or surgically sterile) who have a male partner must have a negative serum pregnancy test result and must agree to one of the following from start of Screening through 30 days after the last study medication administration: use a reliable method of birth control, or monogamous relationship with a male partner of confirmed sterility, or practice complete abstinence.
• Females of non-childbearing potential may be enrolled if it is documented that they are postmenopausal.
• Body weight greater or equal to 50 kg and body mass index (BMI) between 18 and 35 kg/m2, inclusive at Screening.
• Stable medical conditions for 3 months prior to Screening visit (e.g., controlled hypertension, dyslipidemia).
• Willing to follow the protocol requirements and comply with protocol restrictions.
• Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative.

Exclusion Criteria:

• Poorly controlled hypertension despite lifestyle modifications and/or pharmacotherapy.
• Pulmonary disease, including asthma if requiring the use of a β2-Adrenergic bronchodilator, or evidence of clinically significant moderate or severe pulmonary symptoms.
• Clinical signs indicating syndromes such as corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, or Babinski sign.
• Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or meeting DSM-IV diagnostic criteria for psychotic disorders.
• Evidence of any significant clinical disorder or laboratory finding (or in the case of potassium levels below normal range) that renders the participant unsuitable for receiving an investigational drug.
• History of malignant disease, including solid tumors and hematologic malignancies (except basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
• Any clinically significant illness or disease as determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG) and clinical laboratory assessments conducted at Screening.
• Clinically significant abnormalities of ECG, including QTcF > 450 ms, for males and QTcF > 470 ms for females, and/or HR < 50 beats per minute, or evidence of clinically significant bundle branch blocks, as indicated by 12-lead ECG.
• Calculated creatinine clearance of ≤70 mL/min according to the Cockcroft-Gault equation.
• Current use of any prohibited prescription medication (high-dose aspirin, paracetamol or levodopa, β-AR agonists or β-AR blockers, hypnotics or benzodiazepines other than clonazepam, monoamine oxidase inhibitors, opioids ), over-the-counter medication, or herbal supplements/products.
• Prior treatment with any investigational drug ≤90 days prior to dosing (Day 1), or ≤5 half-lives of the drug (whichever is longer), or current enrollment in any other study treatment or disease study, except for observational studies.
• Known or suspected alcohol or substance abuse within the past 12 months and/or positive test for alcohol or drugs of abuse.
• Active suicidal ideation within 3 months prior to study Screening.
• Positive screening test for hepatitis C antibody (HCV Ab) or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] at Screening).
• Positive screening test for human immunodeficiency virus (HIV).
• Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Contraindications to wearing the BioStamp digital device sensors, which include but are not limited to implanted pacemakers, defibrillators, or other active implantable devices.
• Known allergies or hypersensitivities to adhesives or hydrogel.
• Other reasons for which the PI considers it is not in the best interest of the participant to undertake the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CST-103/CST-107 to Placebo; Subjects will receive daily doses of CST-103 co-administered with CST-107 for 14 days, followed by a washout period of no drug for 14 days, followed by matching placebo for CST-103 and matching placebo for CST-107 for 14 days.	Drug: clenbuterol (CST-103), nadolol (CST-107), matching placebo; clenbuterol (CST-103) and matching placebo orange capsules; nadolol (CST-107) and matching placebo white capsules
Experimental: Placebo to CST-103/CST-107; Subjects will receive daily doses of matching placebo for CST-103 co-administered with matching placebo for CST-107 for 14 days, followed by a washout period of no drug for 14 days, followed by daily doses of CST-103 co-administered with CST-107 for 14 days.	Drug: clenbuterol (CST-103), nadolol (CST-107), matching placebo; clenbuterol (CST-103) and matching placebo orange capsules; nadolol (CST-107) and matching placebo white capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT)	Faces with six different basic emotions (happiness, fear, anger, disgust, sadness, surprise) are briefly displayed on a screen and participants are required to indicate the expression of the face via a button-press. Cohort A only.	Days 7 and 14 of each Treatment Period (Two 14-day periods)
Change From Baseline in Cognitive Fluctuations	Dementia Cognitive Fluctuation Scale (DCFS). Number of participants with improvement relative to screening. Cohort B only.	Screening, Days 1 and 14 of each Treatment Period (Two 14-day periods)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in CANTAB Cognitive Assessments	The CANTAB cognitive assessments consists of a series of interrelated computerized tests of memory, attention, and executive function, administered via a touch sensitive screen. This includes the immediate and delayed Verbal Recognition Memory (VRM) recall and recognition tests that measure the ability to encode and subsequently retrieve verbal information.	Days 1, 7, 14 of each Treatment Period (Two 14-day periods)
Digital Wearable Device (BioStamp) - Sleeping Heart Rate	A wireless device that measures physical activity and sleep while at home.	Screening, Days 1-14 of each Treatment Period (Two 14-day periods)
Digital Wearable Device (BioStamp) - Sleeping Heart Rate Variability (HRV)	A wireless device that measures physical activity and sleep while at home.	Screening, Days 1-14 of each Treatment Period (Two 14-day periods)
Digital Wearable Device (BioStamp) - Sleeping Heart Rate Variability (HRV) - Root Mean Square of Successive Differences (RMSSD)	A wireless device that measures physical activity and sleep while at home.	Screening, Days 1-14 of each Treatment Period (Two 14-day periods)

Collaborators and Investigators

• Sponsor: CuraSen Therapeutics, Inc.
• Investigators: Study Director: Chief Medical Officer, CuraSen Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2021
• Primary Completion (Actual): July 4, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: January 29, 2021
• First Submitted That Met QC Criteria: February 1, 2021
• First Posted (Actual): February 4, 2021

Study Record Updates

• Last Update Posted (Estimated): December 2, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Cognition Disorders; Sleep Wake Disorders; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parasomnias; REM Sleep Parasomnias; Cognitive Dysfunction; Mental Disorders; Parkinson Disease; Dementia; Neurodegenerative Diseases; Lewy Body Disease; REM Sleep Behavior Disorder; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Anti-Arrhythmia Agents; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Adrenergic beta-Agonists; Antihypertensive Agents; Sympatholytics; Adrenergic beta-Antagonists; Adrenergic Antagonists; Sympathomimetics; Nadolol; Clenbuterol
• Other Study ID Numbers: CST103/CST107-CLIN-011

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No