The primary objectives of this study are:Part A 1. To characterize the effects of single doses of beta-adrenoceptor (β-AR) agonists CST-101, CST-103 and β AR partial agonist CST-109 on the functional domains of the central nervous…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints are:
Parts A, B, and C
1. Measures of CNS activity captured in the NeuroCart, which include:
a. Saccadic Eye Movement
b. Smooth pursuit eye movement
c. Adaptive tracking
d. Body sway
e. Visual Verbal Learning Test with emotional Valence
f. Stroop test
g. Visual analogue scale (VAS) Bond and Lader
h. VAS Bowdle
i. Electroencephalography (EEG)
j. Pupillometry
k. Dual Task Test
l. Choice Reaction Time Test
m. N-back Test
Secondary outcome
The secondary endpoints are:
1. Adverse events (AEs), electrocardiograms (ECGs), vital signs, laboratory
safety tests (hematology, chemistry, and urinalysis)
2. Heart rate and blood pressure
Background summary
Research from the Shamloo laboratory at Stanford University has demonstrated
that the noradrenergic system, and β-AR agonists in particular, are promising
therapeutic targets for AD. In multiple transgenic mouse models of AD,
xamoterol, a β-AR agonist, enhances cognitive function associated with the
disease (Ardestani 2017, Coutellier 2014, Faizi 2011, Faizi 2012, Salehi 2009).
The laboratory further discovered that, in addition to the cognition-enhancing
effects, xamoterol attenuates three major pathological hallmarks of AD:
beta-amyloid burden, tau pathology, and neuroinflammation (Ardestani 2017).
Collectively, these data suggest that targeting β-AR may have the unique
potential to provide comprehensive therapeutic benefits for the treatment of
AD.
Several epidemiology papers have been published suggesting that treatment with
β-AR agonists is protective against PD (Aaseth 2018, Clark and Vissel 2018,
Gronich 2018, Magistrelli 2019, Mittal 2017, Searles 2018). Additional data
also suggest that the effect of β-AR agonists may generalize to other
neurodegenerative disorders such as mild cognitive impairment and AD
(Chalermpalanupap 2013, Coutellier 2014).
Based on the published effects of β-AR agonists on measures of cognition and
/or neurodegeneration in rodents and humans, this study undertakes an
assessment of the effects of CST-101, CST-103, and CST-109 on measures of CNS
function that are relevant to neurodegenerative disorders.
Study objective
The primary objectives of this study are:
Part A
1. To characterize the effects of single doses of beta-adrenoceptor (β-AR)
agonists CST-101, CST-103 and β AR partial agonist CST-109 on the functional
domains of the central nervous system (CNS), as measured by NeuroCart (a
standardized and comprehensive battery of tests to evaluate drug effects).
Parts B and C
2.To characterize the effects of multiple doses of β-AR agonist (CST-101,
CST-103, or CST-109) on the functional domains of the CNS, as measured by
NeuroCart
Study design
Part A is singled dose randomized 4- way crossover
Part B is a multiple-dose, placebo-controlled, randomized, 2 treatment period,
2-way crossover design with a β-AR agonist tested in Part A
Part C is a multiple-dose, double-blind, randomized, placebo-controlled,
parallel-group design with a selected β-AR agonist tested in Part A
Intervention
CST-101, CST-103 and CST-109
Study burden and risks
While there will be no direct benefits for subjects and patients participating
in this study, the data generated will be valuable and beneficial for
developing β-AR agonist therapies for neurodegenerative diseases.
The adverse events that are expected with use of CST-101, CST-103, and CST-109
for their approved indications are identified in the product monographs
provided as appendices to the Investigator Brochure (IB) and in the summary in
the IB of clinical data on the use of the CST-103 dose that exceed the
monograph doses. The medications will be administered as single doses in Part A
and the β-AR agonist selected for Parts B and C will be administered for 7
days.
2655 Campus Drive Suite 110
San Mateo CA 94403
US
2655 Campus Drive Suite 110
San Mateo CA 94403
US
Listed location countries
Age
Inclusion criteria
Main inclusion criteria healthy volunteers:
1. Males and females aged 35-60 years (inclusive) at the time of informed
consent
2. Unless confirmed to be azoospermic (vasectomized or secondary to medical
cause), males must agree to use a male condom plus partner use of an additional
contraceptive method 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.
3. Females of childbearing potential (i.e., not postmenopausal or surgically
sterile) must agree to one of the following from start of Screening through 90
days after the last study drug administration:
a. use two effective methods of birth control, including hormonal prescription
oral contraceptives, contraceptive injections, contraceptive patch,
contraceptive ring, intrauterine device, barrier method (e.g., condoms,
diaphragm, or cervical cap) or spermicidal foam, cream or gel, or
b. practice complete abstinence, or
c. monogamous relationship with a male partner of confirmed sterility.
4. Body weight equal to or greater than 50 kg and body mass index (BMI) between
18 and 35 kg/m2, inclusive at Screening
5. Participant is free from clinically significant illness or disease as
determined by medical and surgical history, physical examination, 12-lead ECG
and clinical laboratory assessments conducted at Screening and Day -1 as agreed
to by the Investigator and Medical Monitor.
6. No current use of any prescription medication, over-the-counter medication,
or herbal supplements/products during Screening or throughout study, unless
approved by both the Investigator and the Sponsor
7. Able to understand and sign the written Informed Consent Form (ICF)
8. Able to communicate well with the Investigator in the Dutch language and
willing to follow the protocol requirements and comply with protocol
restrictions
Main Inclusion criteria Parkinson patients:
1. Males and females aged 40-75 years (inclusive) at the time of informed
consent
2. Unless confirmed to be azoospermic (vasectomized or secondary to medical
cause), males must agree to use a male condom plus partner use of an additional
contraceptive method 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.
3. Females of childbearing potential (i.e., not postmenopausal or surgically
sterile) must agree to one of the following from start of Screening through 90
days after the last study drug administration:
a. use two effective methods of birth control, including hormonal prescription
oral contraceptives, contraceptive injections, contraceptive patch,
contraceptive ring, intrauterine device, barrier method (e.g., condoms,
diaphragm, or cervical cap) or spermicidal foam, cream or gel, or
b. practice complete abstinence, or
c. monogamous relationship with a male partner of confirmed sterility.
4. Patient who has Parkinson*s disease (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
5. Hoehn & Yahr stage assessed as <=3 during Screening
6. Mini-Mental State Examination (MMSE) score >=26 assessed during Screening
7. If taking medications for PD, patients on stable (>=3 months prior to Day 1)
levodopa/ carbidopa or levodopa/benserazide are allowed. Patients stable on
dopamine agonists or catechol-O-methyltransferase inhibitors for 60 days are
also allowed. Patients are allowed to use β-AR blockers for tremors up to 48
hours before NeuroCart testing. Patients on monoamine oxidase type B inhibitors
are not allowed.
8. Stable medical conditions for 3 months prior to Screening visit (e.g.,
hypertension, dyslipidemia
9. Use of vitamin E (up to 400 IU daily), estrogens, aspirin (81-300 mg daily),
blood pressure medications (except for adrenergic agents), and
cholesterol-lowering agents is allowed if treatment is stable for 3 months
prior to Screening.
10. In generally good health, in the opinion of the Investigator, based on
medical and surgical history, BMI, physical examination, vital signs, 12-lead
ECG, and laboratory values, including hematology and chemistry values
11. Clinical laboratory values within normal limits or, if abnormal, must be
judged to be clinically insignificant by the Investigator
12. Able to understand and sign the written Informed Consent Form (ICF)
13. Able to communicate well with the Investigator in the Dutch language and
willing to follow the protocol requirements and comply with protocol
restrictions
Exclusion criteria
Main exclusion criteria all volunteers:
1. History of any clinically significant disease, as assessed by the
Investigator, including cardiovascular, hepatic, renal, pulmonary, hematologic,
gastrointestinal, endocrine, immunologic, dermatologic, neurologic, metabolic,
psychological, musculoskeletal disease, or malignancies
2. Participants with a history (in the 5 years prior to Screening) 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)
3. A calculated creatinine clearance of <=60 mL/min according to the
Cockcroft-Gault equation
4. Positive screening test for human immunodeficiency virus (HIV)
5. 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). Participants with immunity to hepatitis B (defined as
negative HBsAg and positive hepatitis B surface antibody [HBsAb]) are eligible
to participate in the study.
6. History of drug or alcohol abuse <=12 months prior to Screening, or current
use of more than 21 units of alcohol per week
7. History of nicotine use <=6 months prior to Screening
8. A positive test for drugs of abuse or alcohol during Screening (a repeat per
Investigator discretion is allowed if initial screening is positive) or prior
to Day 1 (unless the prescribed drugs are thought to result in a positive test
for drug abuse)
9. Unwilling or unable to abstain from alcohol from 2 days prior to Day 1 until
end-of-study (EOS) assessments
10. Is demonstrating excess xanthine consumption (more than 8 cups of coffee or
equivalent per day)
11. Clinically significant abnormal clinical laboratory test values, as
determined by the Investigator, or any value of alanine aminotransferase (ALT)
or aspartate aminotransferase (AST) that is more than 1.5 x the upper limit of
normal, or any out-of-range value for serum sodium or potassium that is, in the
opinion of the Investigator, clinically significant. Screening tests may be
repeated once at the discretion of the Investigator.
12. Clinically significant laboratory or ECG abnormality that could be a safety
issue in the study, including QT using Bazett*s or Fredericia*s correction of
QT interval (QTcB or QTcF) >450 msec for males and >470 msec for females
13. History of angina, uncontrolled hypertension, heart failure, coronary
insufficiency, cardiac arrythmias, diabetes mellitus, hyperthyroidism,
convulsion disorders, bronchial asthma, sinus bradycardia and greater than
first degree conduction block, cardiogenic shock
14. Participation in an investigational drug or device study within 3 months
prior to first dosing, or current enrollment in any other study treatment or
disease study
15. Prior treatment with any β-AR agonists or β-AR blockers within the month
prior to study enrollment for healthy subjects
16. Donation or loss of >=500 mL of blood or blood products within 30 days prior
to dosing
17. Any other reason for which the Investigator considers it is not in the best
interest of the participant to undertake the stud
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002252-17-NL |
| CCMO | NL70324.056.19 |