The objective of the present study is to assess the effect of HTL0009936 on cognitive performance in elderly subjects with below average cognitive function. The oral pharmacokinetics of HTL0009936 shows a significant degree of variability between…
ID
Source
Brief title
Condition
- Mental impairment disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability endpoints
- Treatment-emergent (serious) adverse events ((S)AEs)
- Concomitant medication
- Clinical laboratory tests (Haematology, Chemistry, Urinalysis)
- Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic
blood pressure (mmHg))
- Electrocardiogram (ECG) (Heart Rate (HR) (bpm), PR, QRS, QT, QTcB, QTcF)
Pharmacokinetics
A population approach PK model will be developed, describing the plasma
HTL0009936 concentrations over time.
Pharmacodynamics (Part B only)
Adaptive Tracking test
Visual Analogue Scale
N-back test
Verbal visual learning test
Milner MAZE test
Pupil size
Pharmaco-EEG
Leeds Sleep Evalaution Questionnaire
Paired Associates Learning test
Rapid Visual Information Processing test
Spatial Working Memory test
Secondary outcome
• To assess the concentration of HTL0009936 and its R-enantiomer HTL0010042 in
selected samples.
• To undertake preliminary investigations into the metabolite(s) of HTL0009936
in selected and/or pooled samples.
Background summary
Increased life expectancy due to improved healthcare has raised the incidence
and prevalence of neurodegenerative diseases, such as dementia, in the last
decades. The most common cause of dementia is Alzheimer*s disease (AD).
Clinically, AD is characterized by progressive decline of cognitive functions,
particularly memory, leading to impairments of activities of daily living, work
and social life. The hallmark features of AD pathology are neurofibrillary
tangles and amyloid plaques that contain the Aβ peptide.
Research has shown that there is a significant and progressive loss of
cholinergic neurons along with their cortically projecting axons in AD. This
cholinergic degeneration has been correlated to the cognitive decline seen in
AD, and is supported by the temporary cognitive impairment in cognitively
normal subjects induced by administration of the anticholinergic drug
scopolamine and the subsequent reversal by administration of physostigmine, a
cholinesterase inhibitor (AChEI).
To date, no curative treatment is available for AD and patients can only
benefit from drugs targeting symptomatic relief. The primary choice for
symptomatic treatment are AChEIs, such as galantamine, donepezil and
rivastigmine, which delay the breakdown of acetylcholine released into synaptic
clefts, increasing the availability of acethylcholine (ACh) and thereby enhance
cholinergic neurotransmission. However, treatment with AChEIs often leads to
gastrointestinal side effects (e.g. nausea, vomiting and diarrhea) associated
with increased activation of peripherally located ACh receptors, causing dose
limitations and a significant burden for patients.
There are two types of cholinergic receptors, nicotic receptors and muscarinic
receptors. The muscarinic receptors are G-protein-coupled receptors and five
molecular subtypes are known (M1 - M5). The M1 receptors are mainly located in
the central nervous system (CNS) and mediate excitatory effects. Areas of the
brain where these receptors are abundantly expressed include the cortex,
hippocampus and striatum, areas which are also involved in cognitive processes
such as memory and learning. Enhanced cholinergic receptor activation, either
by the use of cholinesterase inhibitors or muscarinic agonists has resulted in
an improved cognitive functioning in different animal models. Unsurprisingly,
this receptor subtype has long been hypothesized to be a potential therapeutic
target for the treatment of cognitive decline in Alzheimer*s disease. Several
studies with transgenic mice lacking the M1 receptor have provided evidence for
the role that the receptor plays in cognitive functioning as the animals showed
impaired memory functioning.
HTL0009936, as a potent and selective M1 receptor agonist, is hypothesized to
enhance cognitive abilities in patients suffering from AD.
Study objective
The objective of the present study is to assess the effect of HTL0009936 on
cognitive performance in elderly subjects with below average cognitive
function. The oral pharmacokinetics of HTL0009936 shows a significant degree of
variability between subjects, which may be a consequence of low oral
bioavailability. Therefore in order to reduce this variability and to ensure
sustained exposure within the CNS over the period of cognitive testing,
HTL0009936 will be given as an infusion by the intravenous route. The infusion
will consist of a 30min loading dose in order to reach the target steady state
plasma concentration followed by a 4.5h maintenance dose designed to maintain
the target steady state concentration.
As this will be the first time in which HTL0009936 will be given IV, the
cognitive assessment part of the study (Part B) will be preceded by assessment
of the safety and PK in normal healthy elderly when given IV (Part A) in order
to design an appropriate well-tolerated dosing regimen for Part B. Target
plasma concentrations in the study will be within the range shown to be well
tolerated after dosing via the oral route.
Part A
• To evaluate the pharmacokinetic profile following short and prolonged IV
administration of HTL0009936 in healthy elderly.
• To evaluate the safety and tolerability following several IV and one oral
dosing regimens of HTL0009936 in healthy elderly.
• To assess an optimized dosing regimen for future sustained exposure of
HTL0009936 in Part B.
• To determine the absolute bioavailability of HTL0009936 after oral dosing.
Part B
• To evaluate the pharmacodynamic profile of three target steady state plasma
concentrations of HTL0009936 in comparison to placebo and a positive comparator.
• To evaluate the pharmacokinetic profile of three dose levels of IV HTL0009936.
• To evaluate safety and tolerability of three dose levels of IV HTL0009936.
Study design
Part A: A four-way sequential open label cross-over study with intravenous and
oral administration of HTL0009936 in healthy elderly male and female subjects
designed to assess safety, tolerability and pharmacokinetics of HTL0009936.
Part B: A five-way randomized, double-blind, placebo and positive comparator
controlled cross-over study of IV HTL0009936.
Intervention
In Part A of the study HTL0009936 will be administered IV and PO. In Part B
both HTL0009936 and physostigmine will be administered.
Study burden and risks
Burden:
The burden for the participants includes the time investment for the briefing,
screening, cognitive evaluation (Part B of the study), the occasions and the
follow-up visit. Furthermore, subjects are asked to adhere to various lifestyle
regulations. Blood and urine will be collected during the screening, occasions
and the follow-up visit. Participants in both parts of the study will be
exposed to an infusion for up to 5 hours. In Part A of the study, this infusion
comprises only HTL0009936 in various dosages, as well as the oral occasion
where the participants will be administered HTL0009936 in the form of a drink.
In part B of the study physostigmine and placebo will also administered
intravenously next to HTL0009936.
Risk:
A start dose of 0.1 mg by 30 minute IV infusion is proposed, being 10-fold
below the first-in-man oral study start dose of 1 mg and 1000-fold below the
well tolerated 100 mg oral dose. Venapuncture and the insertion of an IV drip
could result in bruising. Fasting and refraining from caffeine could result in
symptoms such as headache or nausea.
Broadwater Road BioPark
Hertfordshire AL7 3AX
GB
Broadwater Road BioPark
Hertfordshire AL7 3AX
GB
Listed location countries
Age
Inclusion criteria
1.Healthy male and female subjects from 65 and older, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis;;2. BMI between 18 and 34 kg/m2, inclusive;;3. Ability to communicate well with the investigator in the Dutch language; ;4. Female participants should be post-menopausal;;5. Able to participate and willing to give written informed consent and to comply with the study restrictions; and;6. Intermediate (IM) or extensive (EM) metabolizer as determined by CYP2D6 genotype.;Additional inclusion criteria for Part B of the study only;1. A score of <=-1 SD on at least one of the following screening tests: 15-word learning test (memory), category fluency; animals (executive functioning) and adaptive tracking (attention);;2. Willing and able to perform the cognitive tests, as evidenced by performance on the training session of the cognitive tests.
Exclusion criteria
1. Legal incapacity or inability to understand or comply with the requirements of the study;;2. Clinically relevant history of abnormal physical or mental health interfering with the study as determined by medical history taking and physical examinations obtained during the screening visit and/or at the start of the first study day for each period as judged by the investigator;;3. Any disease associated with cognitive impairment, including but not limited to schizophrenia and dementia;;4. Clinically relevant abnormal laboratory results, ECG and vital signs, or physical findings at screening and/or at the start of the first study day for each period;;5. Systolic blood pressure greater than 140 or less than 90 mm Hg, and diastolic blood pressure greater than 90 or less than 50 mm Hg;;6. Notable resting bradycardia (HR < 45 bpm) or tachycardia (HR > 100 bpm) at screening or baseline visit;;7. A QTcF > 450 or < 300 msec at resting ECG at screening or baseline visit; ;8. Personal or family history of congenital long QT syndrome or sudden death;;9. Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening;;10. Aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase (GGT) or total bilirubin levels >1.5 times the upper limit of normal at screening;;11. Evidence of significant renal insufficiency, indicated by a glomerular filtration rate lower than the lower limit of normal (related to age) at screening;;12. Presence or history (within 3 months of screening) of alcohol abuse confirmed by medical history, or daily alcohol consumption exceeding 2 standard drinks per day on average for females or exceeding 3 standard drinks per day on average for males (1 standard drink = 10 grams of alcohol), or a positive breath alcohol test at screening or upon admission to the Clinical Research Unit, and the inability to refrain from alcohol use from 24 hours before screening, dosing and each scheduled visit until discharge from the clinical research unit;;13. Use of tobacco and/or nicotine-containing products within 90 days of dosing;;14. Habitual and heavy consumption of caffeinated beverages (more than 8 cups of coffee or equivalent/day) at screening and/or unable to refrain from use of (methyl) xanthine (e.g. coffee, tea, cola, chocolate) from 24 hours prior to dosing until discharge from the CRU;;15. Positive urine drug screen (UDS) or alcohol or cotinine test at screening and/or pre-dose;;16. Concomitant use of drugs that are metabolised by and/or are inhibitors of CYP2D6 (e.g., quinidine, paroxetine, fluoxetine) or inhibitors/inducers of CYP3A4 (e.g., ketoconazole, ritonavir) from 21 days prior to study drug administration;;17. Concomitant use of drugs that are substrates for the organic cation transporter 2 (OCT 2), including amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin and dofetilide;;18. Intake of any food or any drinks containing cranberry, pomegranate, star fruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from these fruits) within 3 days before admission to the CRU and while subjects are confined to the CRU;;19. Subject is unable to refrain from the use of concomitant medication which, in the opinion of the investigator, interferes with their ability to participate in the trial, from 7 days prior to dosing until the final follow-up study visit;;20. Female subjects of child-bearing potential;;21. History of severe allergies, or history of an anaphylactic reaction to prescription or non-prescription drugs or food (non-active hay-fever is acceptable);;22. History of epilepsy or seizures of any kind at any time;;23. History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drugs;;24. Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug or more than 4 times per year;;25. Donation or loss of blood of more than 500 mL within 3 months (males) or 4 months (females) prior to screening;;26. Any other concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study.;Additional exclusion criteria Part B only:;1. A score of >0 on the CDR;;2. A score of <24 on the MMSE;;3. A score of >13 on the BDI-II;;4. Are shift workers or have crossed or will cross more than 2 time zones within 48 hours prior to occasion 1, Day 1 until admission to occasion 5;;5. Have regular napping (>=2 daytime naps/week by history), with a nap defined as any sleep episode lasting longer than 1 hour outside of normal bedtime hours (according to subjects* reports);;6. Show symptoms consistent with a sleep disorder or history of same.
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004123-43-NL |
| CCMO | NL51371.056.14 |