| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Parkinson’s Disease with REM sleep behaviour disorder, Mild Cognitive Impairment, Dementia with Lewy Bodies and Parkinson’s Disease Dementia. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with Parkinson's disease and patients with memory problems. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012284 |
| E.1.2 | Term | Dementia due to Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009846 |
| E.1.2 | Term | Cognitive impairment |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067889 |
| E.1.2 | Term | Dementia with Lewy bodies |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to identify a CNS signal in one of the planned pharmacodynamic measures (emotional facial processing, cognitive fluctuations) after multiple doses of CST-103 co-administered with CST-107 in subjects with neruodegenerative diseases.
The objective is to identify an improvement in cognition, for example in learning, thinking and remembering, a CNS signal in one of the planned pharmacodynamic measurements after multiple oral doses of CST-103 in the presence of CST-107 in four populations of subjects with neurodegenerative disorders. This includes patients with Parkinson's Disease (PD) and REM Sleep Behaviour Disorder (RBD+PD), Mild Cognitive Impairment (MCI), Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB).
The primary objective for Cohort A population is a change in emotional facial recognition, a measure of mood. The primary objective for the Cohort B population is to assess the change in cognitive fluctuations. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives for all subjects include the comparison of the effect of CST-103 co-administered with CST-107 with that of placebo on the following:
Cognition, sleep, pupillary reactivity, mood assessment, safety and tolerability of CST-103 co-administered with CST-107,the pharmacokinetic (PK) profiles of CST-103 and CST-107.
The exploratory objectives are to characterise the effects of CST-103 co-administered with CST-107 on inflammatory and neurodegenerative biomarkers. In addition the effects of these drugs will be examined on performance in a sustained attention task and on freezing of gait in the subjects with Parkinson's disease.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort A:Subjects with RBD+PD:
1.Male or female subjects ≥ 40 and ≤ 80 years of age, at time of informed consent.
2.Subject diagnosed with Parkinson’s Disease, as defined by the United Kingdom Parkinson Disease Brain Bank criteria, associated with REM sleep behaviour disorder (RBD+PD), diagnosed according to the International Classification of Sleep Disorders, Third Edition (ICSD-3) (albeit documentation by polysomnography is not required) and positive response to the REM Sleep Behaviour Disorder Single-Question Screen (RBD1Q).
3.Subject who is Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during “On” period as documented in the 3 months prior to Screening or completed at Screening.
4.Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 28.
5. Intentionally left blank
Subjects with MCI:
6.Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.
7.Subjects who meet the criteria for amnestic Mild Cognitive Impairment (MCI) as per the National Institute on Aging-Alzheimer's Association core clinical criteria.
8.Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26.
9.No dementia according to the International Classifications of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV.
10.A memory complaint reported by the subject or his/her partner, family member or caregiver
11.A score of greater than or equal to one standard deviation below age and educational norms in the Digit Symbol Substitution Test (DSST) during Screening.
12.Cognitive decline not primarily caused by vascular, traumatic, or medical problems (alternative causes of cognitive decline are ruled out).
13.Intentionally left blank
Cohort B: Subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD):
14.Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.
15.A diagnosis of dementia associated with Dementia with Lewy Bodies.
16.Documented cognitive fluctuations endorsed on the Dementia Cognitive Fluctuation Scale (DCFS) with a combined score of >8 in items 4, 11, 12 and 14.
17.Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26.
18.Subject having informant or caregiver throughout the study who will submit written consent to cooperate with this study, who routinely 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.
19.Subject who is Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during “On” period as documented in the 3 months prior to Screening or completed at Screening.
20.Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI.
For ALL Subjects:
21.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.
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a condom during each episode of penile-vaginal penetration until after the Follow-Up Visit.
22.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:
a.use a reliable method of birth control (refer to protocol section 5.6), or
b.monogamous relationship with a male partner of confirmed sterility, or
c.practice complete abstinence (refer to protocol section 5.6).
23.Females of non-childbearing potential may be enrolled if it is documented that they are postmenopausal (refer to protocol section 5.6).
24.Body weight greater or equal to 50 kg and body mass index (BMI) between 18 and 35 kg/m2, inclusive at Screening.
25.Stable medical conditions for 3 months prior to Screening visit (e.g., controlled hypertension, dyslipidemia).
26.Willing to follow the protocol requirements and comply with protocol restrictions.
27.Capable of providing informed consent and complying with study procedures (completion of self-assessment rating scales and use of wearable devices). Subjects who are unable to provide consent may use a Legally Authorized Representative
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| E.4 | Principal exclusion criteria |
1.Subjects with poorly controlled hypertension despite lifestyle modifications and/or pharmacotherapy.
2.Subjects with pulmonary disease, including asthma if requiring use of a β2-adrenergic bronchodilator, or evidence of clinically significant moderate or severe pulmonary symptoms.
3.Clinical signs indicating syndromes such as corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontotemporal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, or Babinski sign.
4.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, such as Schizophrenia or Bipolar Disorder, or have unstable concomitant psychiatric symptomatology that is not believed by the Investigator to be associated with PDD or DLB.
5.Evidence of any significant clinical disorder or laboratory finding (or in the case of potassium levels below the normal range)that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine (excluding managed hypo and hyperthyroidism), metabolic, renal or other systemic disease or laboratory abnormality.
6.Participants with a 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).
7.Any clinically significant illness or disease (apart from those typically associated with NDD) as determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG) and clinical laboratory assessments conducted at Screening.
8.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 in a supine position at Screening or during the Lead-In Period.
9.A calculated creatinine clearance of ≤70 mL/min according to the Cockcroft-Gault equation.
10.Current use of any prohibited prescription medication, over-the-counter medication, or herbal supplements/products (listed in protocol section 5.4), during Screening or throughout study, unless approved by both the Investigator and the Sponsor Medical Monitor.
11. Known hypersensitivity to Spiropent (clenbuterol), Corgard (nadolol) or intolerance to lactose. Subjects with hereditary galactose intolerance (e.g., galactosemia, lactase deficiency or glucose galactose malabsorption) should be excluded.
12.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.
13.Prior treatment with any β-AR agonists or β-AR blockers (includes oral meds, IV or inhaled) or any meds that impact adrenergic signalling within the last month prior to Screening.
14.Known or suspected alcohol or substance abuse within the past 12 months and/or positive test for alcohol or drugs of abuse at Screening or Day 1.
15.Suicidal ideation with actual intent or plan (“Yes” answer on the C-SSRS ideation items 4 or 5) within 3 months prior to study Screening.
16.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). Subjects with immunity to hepatitis B (defined as negative HBsAg and positive hepatitis B surface antibody [HBsAb]) are eligible to participate in the study.
17.Positive screening test for human immunodeficiency virus (HIV).
18.Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
19.Known hypersensitivities to adhesives or hydrogel.
20. Females who are breastfeeding.
21.Any other reason for which the PI considers it is not in the best interest of the participant to undertake the study.
22. Inability to undergo a clinical MRI of the brain due to claustrophobia, inability to lie supine for a prolonged time period, or other contraindications to undergoing an MRI of the brain including, but not limited to, pacemakers; implantable cardioverter defibrillators; cochlear implants; cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; and, other magnetic, electronic or mechanical implants or clinical findings that in the judgment of the investigator would pose a potential hazard in combination with MRI. (NOTE: this is a procedural exclusion, not a study exclusion.)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints include:
Cohort A
Comparison of the effects of CST-103 co-administered with CST-107 vs placebo on change in Negative Emotional Bias in the Facial Expression Recognition Task.
Cohort B
Comparison of the effects of CST-103 co-administered with CST-107 vs placebo on Cognitive Fluctuations as measured by:
1. Spectral analysis of waking EEG
2. Pupillometry
3. Dementia Cognitive Fluctuation Scale (DCFS) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol. |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints will compare the effect of CST-103 co-administered CST-107 with that of placebo on the following:
1. Verbal fluency test (alphabet & category) and CANTAB cognitive assessments, which include the following:
• Reaction Time (RTI)
• Rapid Visual Information Processing (RVP)
• Verbal Recognition Memory (VRM) Phase I
• Adaptive Tracking Task (ATT)
• Paired Associates Learning Task (PAL)
• Stop Signal Task (SST)
• Delayed Verbal Recall
2. Assessment of sleep using the Epworth Sleepiness Scale (ESS)
3. Change in pupillary diameter as measured using the pupillary light reflex test
4. Geriatric Depression Scale (GDS)
5. Adverse events (AE), electrocardiograms (ECGs), vital signs, laboratory safety tests (hematology, chemistry and urinalysis).
6. Plasma PK parameters of CST-103 and CST-107 (including Cmax, tmax, AUCt, AUCinf, t1/2) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| New Zealand |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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