Primary objectivesPart 1To evaluate the single dose safety and tolerability of donepezil 10 mg when administered with placebo, glycopyrrolate or trospiumPart 2To evaluate the safety and tolerability of donepezil when given with concomitant placebo,…
ID
Source
Brief title
Condition
- Structural brain disorders
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety, Tolerability and Pharmacokinetics
Secondary outcome
N.A.
Background summary
Alzheimer*s disease 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, 2015]. No new chemical entities
have been approved by the U.S. Food and Drug Administration (FDA) for the
treatment of Alzheimer*s disease since 2003 or by the European Medicines Agency
(EMA) since 2002.
Study objective
Primary objectives
Part 1
To evaluate the single dose safety and tolerability of donepezil 10 mg when
administered with placebo, glycopyrrolate or trospium
Part 2
To evaluate the safety and tolerability of donepezil when given with
concomitant placebo, glycopyrrolate, or trospium for 10 days.
Part 3
To evaluate the concentration of glycopyrrolate into the cerebrospinal fluid
Secondary objectives
Part 2
To characterize the pharmacokinetics of donepezil and glycopyrrolate when given
concomitantly.
To characterize the pharmacokinetics of donepezil and trospium when given with
concomitantly.
To evaluate the effect of glycopyrrolate and trospium on donepezil
pharmacodynamics using polysomnography.
To evaluate the effect of glycopyrrolate and trospium on donepezil
pharmacodynamicsphrmacodynamics by using a smell identification test.
Part 3
To evaluate the safety and tolerability of glycopyrrolate
To characterize the plasma pharmacokinetics of glycopyrrolate
Study design
This is a three-part study. Subjects are allowed to participate in only one
part of the study. Parts 1 and 2 are partially or fully blinded and will be
conducted sequentially. Part 3 is open label and will be conducted after
completion of Part 2.
Part 1
Part 1 is a randomized, partially blinded, single dose study in elderly
subjects. Subjects will be admitted to the clinical unit on a convenient time
on Day -1 and remain in the unit until the afternoon of Day 2 but may stay in
the unit longer if medically justified. Each subject will be randomized to one
of the following treatments:
* Single dose 10 mg donepezil + placebo (n=8)
* Single dose 10 mg donepezil + glycopyrrolate 2 mg (n=8)
* Single dose 10 mg donepezil + trospium XR 60 mg (n=8)
six subjects (2 of each treatment) will be dosed first. After at least 48
hours of observation, the additional subjects will be dosed.
A follow-up visit will occur between 7 and 14 days after the treatment.
Safety assessments will be collected throughout the treatment period. Each
subject will participate for approximately 7 weeks (30 days screening period,
approximate 1-week study period, 7-14 day follow-up period).
After the completion of Part 1, the safety and tolerability data will be
reviewed by the Study Team, consisting of members from the CRO and the
Sponsor. The initiation of Part 2 will depend upon agreement by the PI and
Sponsor that the data are adequate to proceed to the multiple dose phase.
Part 2:
Part 2 is a randomized, double blind, repeat dose study in healthy, elderly
subjects. Subjects will be randomized to one of the following study treatments:
* donepezil 5 mg QD+ placebo BID for 10 days (n=12)
* donepezil 10 mg QD + glycopyrrolate 1mg BID x 10 days (n=12)
* donepezil 10 mg QD + glycopyrrolate 2mg QD x 10 days (n=12)
* donepezil 10 mg QD + trospium XR 60mg QD x 10 days (n=12)
Subjects will be admitted to the clinical unit on a convenient time on Day -1
and will remain in the clinical unit until Day 11 but may stay in the unit
longer if medically justified. Safety assessments will be performed throughout
the study and PK samples will be obtained on Day 1 pre-dose and over a 24-hour
period on day 10 of treatment.
Each subject will participate for approximately 8 weeks (30 days screening
period, approximate 2-week study period, 7-14 day follow-up period).
Part 3:
Part 3 is an open label, repeat dose study in elderly subjects. Subjects will
receive the following treatment:
* glycopyrrolate 2 mg once daily for 3 days (n=3)
Subjects will be admitted to the clinical unit on a convenient time on Day -1
and will remain in the clinical unit for the duration of the trial. Safety
assessments will be performed throughout the study and PK samples will be
obtained on Day 1 pre-dose and over a 24-hour period on day 3 of treatment. A
CSF sample will be collected between 2 and 6 h after dosing on Day 3, Subjects
can be discharged from the unit on Day 4 if medically justified.
Each subject will participate for approximately 7 weeks (30 days screening
period, approximate 1-week study period, 7-14 day follow-up period).
Intervention
The study will start with a screening visit. During the screening visit,
standard medical assessments, including safety laboratory tests (blood draw,
urine collection), alcohol breath test, urine drug screen, physical
examination, ECG and a vital signs measurement will be performed.
Subjects will enter the clinic on day -1. Day -1 is the day before dosing.
Subjects will receive a single dose of 10mg donepezil plus either placebo, 2mg
glycopyrronium or 60mg trospium. Subjects will stay for 3 days (2 nights).
Subjects will leave the clinic at the end of day 2. A followup visit will be
planned after 7 - 14 days after dosing.
Study burden and risks
Side effects Donepezil: Very often diarrea, nausea and headache. Often: cold,
anorexia, hallucinations, agitation, aggresive behaviour, fainting, dizziness,
insomnia, vomitting, adbdominal discomfort, skin rash, itch, musle spasms,
incontinence, fatigue, pain. Sometimes: seizuresm bradycardia, gastrointestinal
bleeding, gastric and duodenal ulcers or a slight increase in serum creatine
kinase in muscles. Rarely: extrapyramidal symptons, atrioventricular block or
liver disease (hepatitis). Very rare: neuroleptic syndrome or rhabdomyolysis.
Side effects Glycoppyronium: dry mouth, decreased sweating, urinary symptoms,
blurred vision, tachycardia, mydriasis, cycloplegic (paralysis of the
adaptability of the eye), glaucoma, loss of taste, headache, nervousness,
mental confusion, drowsiness, weakness, dizziness, insomnia, nausea, vomiting,
constipation, bloating, impotence, decreased lactation, severe allergic
reaction or hypersensitivity including anaphylaxis, hives and other skin
disorders.
Side effects Trospium: Very often: dry mouth. Often: dry eyes, stomach
discomfort, constipation, stomach ache, air in abdomen, nausea and a dry nose.
Sometimes: flatulence.
The risks are small. The medication will be given in a controlled surrounding.
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.
Lumbur punction risks:
The most common side effect after an epidural is headache. This occurs in 2.6%
of the patients, but mainly by young people. Complaints occur about 24 * 48
hours after the epidural, caused by leakage of spinal cord fluid (CSF) after
removal of the needle. The headache is mostly located in the front and the back
of the head, headache will reduce by lie horizontally. Possible other side
effects are nausea, vomiting, dizziness, double vision and tinnitus. The pain
disappears mostly within 7 days and can be treated with paracetamol and
caffeine. In serious cases it can be decided to close the puncture with an
injection of subject`s own blood op the place where the needle has been placed
into the back. This will be done in the hospital. There is a small change that
via the needle, used for the epidural, an infection of the skin, subcutaneous
tissue or the vertebra arises. The epidural will be performed under sterile
circumstances which makes this a rather small change.
During placement of the needle, nerve roots can be touched by the needle. This
is notices as a feeling of electricity in one of the legs; this feeling of
electricity is not permanent.
Clarendon House 2 Church Street
Hamilton HM 11
BM
Clarendon House 2 Church Street
Hamilton HM 11
BM
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 that 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 mlU/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 1 month after 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 urine drug/alcohol breath screen at screening and Day -1. A minimum list of drugs that will be screened for in included in Section 7.5.4.
2. A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at screening.
3. A positive test for human immunodeficiency virus (HIV) antibody at screening.
4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct bilirubin values greater than 1.25x the upper limit of normal (ULN) at screening and Day -1. A single repeat is allowed for eligibility determination.
5. Moderate or heavy users of tobacco- or nicotine-containing products within 1 month prior to screening. Light smokers (< 5 cigarettes per day or equivalent) may be enrolled.
6. History of regular alcohol consumption within 6 months of the study defined as:
* An average weekly intake of >21 drinks/week for men or >14 drinks/week for women.
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. Other than those medications outlined in Section 6.9.1, use of prescription or non-prescription drugs, 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. Vitamins must be discontinued 2 days prior to the first dose of study medication.
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 first 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 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 90-150mmHg, diastolic blood pressure is outside the range of 60-100mmHg or heart rate is outside the range 45-100 bpm.
20. Positive orthostatic challenge test at screening
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 | EUCTR2016-003976-27-NL |
| CCMO | NL59399.056.16 |