Primary:To establish the safety and tolerability of rivastigmine when given with concomitant glycopyrrolate at an accelerated dose escalation schedule up to 12 mg BID.To establish the safety and tolerability of rivastigmine when given with…
ID
Source
Brief title
Condition
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Number of subjects completing full dose escalation
* Number of subjects in each group completing the 6 mg BID dosing period
Secondary outcome
* Highest dose achieved before stopping due to intolerability
* Nausea score by visual analog scale
* Number of vomiting episodes and time to first vomiting episode
* Abdominal pain score by visual analog scale
* Number of diarrhea episodes
* Percent of subjects reporting nausea
* Percent of subjects reporting vomiting
* Percent of subjects reporting diarrhea
* Percent of subjects reporting dizziness
* Other AEs
* General safety and tolerability parameters also include adverse events,
clinical laboratory, electrocardiogram (ECG), and vital sign assessments
* Plasma PK parameters of rivastigmine and metabolite as data permit
* Change from baseline in REM sleep parameters, including shortening of REM
latency, increase in REM density and increase in the percentage duration of REM
sleep during the night
* Spectral parameters in non-REM sleep (spindle power, spindle density)
* Change from baseline in nausea intensity based on a Visual Analog Scale (VAS)
assessment
* Change from baseline in abdominal pain based on a VAS assessment
Background summary
Alzheimer*s disease (AD) is a progressive neurodegenerative disorder. According
to the Alzheimer*s Association, a leading voluntary health organization in
Alzheimer*s disease care, support and research, Alzheimer*s disease affects
approximately 5.3 million people in the United States, and it is estimated that
between 70% and 90% of those patients are classified as having mild-to-moderate
Alzheimer*s disease [Alzheimer*s Association, 2013].
Dementia with Lewy bodies (DLB), also termed major neurocognitive disorder with
Lewy bodies is a progressive neurocognitive illness characterized
pathologically by the presence of diffuse clusters comprised of alpha synuclein
and other proteins that aggregate in the brain and disrupt cognitive function
(McKeith et al., 1996; McKeith et al., 2005). DLB is considered to be the
second most prevalent cause of degenerative dementia in the elderly population
(McKeith, 2004), accounting for up to 15 * 25% of dementia presentations
(McKeith et al., 2000). While few studies of the exact prevalence of DLB have
been published, the Lewy Body Dementia Association estimates that 1.4 million
individuals are affected by Lewy body dementia in the US alone.
One of the pathophysiological hallmarks of AD and DLB is reduced cholinergic
neurotransmission, based on the degeneration of key anatomical areas, which
provide acetylcholine. These are primarily the Nucleus basalis Meynert (NBM)
and, of particular relevance for cholinergic activation of the hippocampus, the
medial septal area (MSA). As the hippocampus is primarily responsible for
memory task the MSA could play a key role a decline in memory.
No new chemical entities have been approved by the U.S. Food and Drug
Administration (FDA) for the treatment of AD since 2003 or by the European
Medicines Agency (EMA) since 2002. There are currently no approved treatments
for DLB. Thus, new treatments or strategies that can improve or delay the
decline in cognitive function are warranted.
Study objective
Primary:
To establish the safety and tolerability of rivastigmine when given with
concomitant glycopyrrolate at an accelerated dose escalation schedule up to 12
mg BID.
To establish the safety and tolerability of rivastigmine when given with
concomitant trospium at an accelerated dose escalation schedule up to 12 mg BID.
Secondary:
To characterize the pharmacokinetics of rivastigmine when given with
concomitant glycopyrrolate or trospium at an accelerated dose escalation
schedule up to 12 mg BID.
To characterize the pharmacodynamics of rivastigmine when given with
concomitant glycopyrrolate or trospium at an accelerated dose escalation
schedule up to 12 mg BID.
Study design
This study will be partially blinded where subjects will be randomized to
rivastigmine plus glycopyrrolate or trospium. Rivastigmine will not be
blinded. However, subjects and the Investigator will be blinded to the
concomitant medication. In both parts, subjects will have a screening visit
within 30 days of first dose.
Twenty-four subjects will be randomized to receive rivastigmine BID plus
glycopyrrolate 2 mg BID or trospium 60 mg QD on an accelerated rivastigmine
dose escalation schedule (12 subjects per arm) starting at 1.5 mg BID and
escalating every three days for the first 4 doses, and every 6 days for the
remaining 4 doses with a maximum dose of 12 mg BID. Subjects will be admitted
to the clinical unit the day before the first rivastigmine dose and will remain
in the unit for the duration of the rivastigmine dosing.
PK samples will be collected over a 12-hour period after the last morning dose
of the 6 mg and 12 mg BID dosing periods if they reach that level of dose
escalation. Trough samples will be collected the morning prior to each dose
escalation. Subjects will return to the clinic for a follow-up visit 7 to 10
days after their last dose of rivastigmine.
The following assessments will be completed:
* Subjects will undergo a polysomnographic assessment three times: once before
the first administration of study medication (overnight from Day -1 to Day 1 as
baseline) and then again after the final evening dose of the 3 mg rivastigmine
BID dose and the 6 mg BID rivastigmine dose.
* Subjects will complete a 100-mm VAS to assess nausea at multiple timepoints
on the mornings of the first day of multiple dose escalations.
* Subjects will complete a 100-mm VAS to assess abdominal pain at multiple
timepoints on the mornings of the first day of multiple dose escalations.
Study burden and risks
The dose levels of the study drugs are selected on the basis of the clinical
experience with these drugs. The risk to health at these dose levels is limited
but you may experience one of the in the ICF mentioned side-effects or other
symptoms not previously reported. Your health will be closely monitored during
the study to minimize these risks. If you experience any side effects, the
research physician will treat these where necessary. If new information becomes
available about the safety of the study drug, you will be informed as soon as
possible.
The blood collection procedure is not dangerous, but may cause discomfort or
bruising. Occasionally, fainting, bleeding or an infection at the blood
sampling site can occur.
c/o Vischer AG, Aeschenvotstadt 4 c/o Vischer AG, Aeschenvotstadt 4
Basel CH-4010
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c/o Vischer AG, Aeschenvotstadt 4 c/o Vischer AG, Aeschenvotstadt 4
Basel CH-4010
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Listed location countries
Age
Inclusion criteria
1. Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if, in the opinion of the Investigator, the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. The Medical Monitor may be consulted as needed.
2. Male or female age 55 and above at screening.
3. A female subject is eligible to participate if she is of:
* Non-childbearing potential defined as pre-menopausal females with a documented bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries) or hysterectomy; hysteroscopic sterilization, or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 mIU/ml is confirmatory]. Documented verbal history from the subject is acceptable.
* Child-bearing potential and agrees to use one of the contraception methods listed in Section 5.6.1 for an appropriate period of time (as determined by the product label or Investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit.
4. Male subjects must agree to use one of the contraception methods listed in Section 5.6.1. This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study medication.
5. Body weight * 50 kg for men and * 45 kg for women and Body Mass Index within the range 18.5 31.0 kg/m2 (inclusive).
6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Exclusion criteria
1. The subject has a positive drug/alcohol screen at screening or Day 1. A minimum list of drugs that will be screened for is included in Section 7.3.4.
2. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result at screening.
3. A positive pre-study test for human immunodeficiency virus (HIV) antibody.
4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct bilirubin values greater than 1.25x the upper limit of normal (ULN) at screening or Day 1. A single repeat is allowed for eligibility determination.
5. Current use of tobacco/nicotine/vaping/e-cig/ products within 1 month prior to screening.
6. History of regular alcohol consumption within 6 months of the study defined as:
* An average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits.
7. The subject has received an investigational product (including placebo) within the following time period prior to the first dosing day in the current study: 60 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
8. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John*s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety (Section 6.9.2).
9. Consumption of Seville oranges or grapefruit (or their juices) from 7 days prior to the first dose of study medication.
10. History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
11. If heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
12. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 60 day period.
13. Pregnant females as determined by positive serum or urine human chorionic gonadotropin test at screening or prior to dosing.
14. Lactating females.
15. Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy, function, or motility, hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of cholecystectomy, peptic ulceration, inflammatory bowel disease or pancreatitis should be excluded.
16. History of significant pulmonary, renal, gastrointestinal, ophthalmologic, genitourinary, or hepatic diseases.
17. History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting surgery or percutaneous transluminal coronary angioplasty or any clinically significant cardiac disease.
18. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination):
Heart rate <45 and >100 bpm
PR Interval <120 and >220 msec
QRS duration <70 and >120 msec
QTcF interval >450 msec ;* Any conduction abnormality (including but not specific to AV block [2nd degree or higher], Wolff Parkinson White syndrome.
* Sinus pauses > 3 seconds.
19. The subject*s systolic blood pressure is outside the range of 90-150 mmHg, diastolic blood pressure is outside the range of 60-100 mmHg or heart rate is outside the range 45-100 bpm.
20. Positive orthostatic challenge test at screening.
21. Recent travel (less than seven days) with a time change greater than 1 hour.
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 | EUCTR2017-002010-31-NL |
| CCMO | NL61990.056.17 |