A study to investigate the association between the acute response and long-term clinical response to galantamine in patients with mild to moderate Alzheimer’s Disease

ISRCTN ISRCTN82825745
DOI https://doi.org/10.1186/ISRCTN82825745
EudraCT/CTIS number 2010-021152-25
Secondary identifying numbers NL33145.02910
Submission date
21/08/2019
Registration date
29/08/2019
Last edited
31/10/2022
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Background and study aims
Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer’s Disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aim to investigate the acute pharmacodynamic effects of a single dose administration of galantamine on central nervous system function in patients with mild to moderate Alzheimer's Disease and its potential to predict long-term treatment response

Who can participate?
Patients with Alzheimer's disease

What does the study involve?
Participants will receive treatment with galantamine for six months. Participants will also take part in a number of mental health assessments at the start and end of the treatment.

What are the possible benefits and risks of participating?
There is a 10 per cent chance of side effects. Nausea and vomiting are the most prevalent side effects of galantamine. Application of the indwelling catheter to monitor the concentrations of galantamine can be painful. The treatment with galantamine is identical to the usual care that would be given if subjects did not participate in this study.

Where is the study run from?
Centre for Human Drug Research, Netherlands

When is the study starting and how long is it expected to run for?
June 2011 to October 2014

Who is funding the study?
The Netherlands Organisation for Health Research and Development (ZonMw)

Who is the main contact?
Dr Geert Jan Groeneveld,
GGroeneveld@chdr.nl

Contact information

Dr Geert Jan Groeneveld
Scientific

Zernikedreef 8
Leiden
2333 CL
Netherlands

ORCiD logoORCID ID 0000-0002-4655-6667
Phone +31 (0) 71 5246 400
Email GGroeneveld@chdr.nl

Study information

Study designSingle-centre double-blind placebo-controlled two-period crossover intervention study
Primary study designInterventional
Secondary study designRandomised cross over trial
Study setting(s)Other
Study typeTreatment
Participant information sheet Not available in web format, please use contact details to request a participant information sheet.
Scientific titleStudy to investigate the association between the response to a cholinergic challenge with galantamine and the clinical response to subsequent treatment with galantamine in patients with mild to moderate Alzheimer’s Disease
Study objectives1. There is a correlation between the pharmacodynamic effects of a single dose of galantamine and the clinical response to treatment with galantamine during a 6-month period in patients with mild to moderate Alzheimer's Disease
2. There is a difference in pharmacodynamic effects of a single dose of galantamine between responders and non-responders to treatment with galantamine during a 6-month period in patients with mild to moderate Alzheimer's Disease
Ethics approval(s)1. Approved 21/10/2010, Medical Ethics Committee of the VU University Medical Center (Medisch Ethische Toetsingscommissie VU Medisch Centrum, De Boelelaan 1117, 1081 HV Amsterdam; subcom-ethiek.org@vumc.nl; +3120-4443488), ref: NL33145.02910
2. Approved 23/05/2013, Medical Ethics Committee of the Clinicii de neurologie a Spitalului Universitar de Urgenta (Comisia Nitionali de Etici pentru Studiu Cllinica l Medicamettului, Adresa: S tr.A v. SanAtescnur .48, sect.1 , Bucurest, +40 314051076), ref: 35528C/04.02.2013
Health condition(s) or problem(s) studiedAlzheimer's Disease
InterventionSingle-centre double-blind placebo-controlled two-period crossover intervention study with a cholinergic challenge in patients with mild to moderate Alzheimer's Disease.

The challenge will consist of one daily dose of 16 mg galantamine or placebo. All patients are subsequently treated with open-label galantamine for a period of six months.

This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate patients in a double-blind, placebo-controlled cross-over fashion. Acute effects were monitored up to 5 hours after administration with the use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care.

After 6 months of galantamine treatment, patients were categorized as either responder or non-responder based on their scores on cognitive tests (neuropsychiatric change). The correlations between the galantamine challenge effect on pharmacodynamic measures and the cognitive and neuropsychiatric change from baseline to month 6 will be determined. Also, responders and non-responders after 6 months of treatment will be defined based on the cognitive and neuropsychiatric outcome at month 6, and the difference in galantamine challenge effects on pharmacodynamic measures will be determined. It will be attempted to develop a PK/PD model for the effects of galantamine on pharmacodynamics in patients with mild to moderate Alzheimer's Disease.

The study has a 2-way cross-over randomized design, i.e. 50% of the subject received placebo and galantamine and 50% received galantamine and placebo in reversed order. The randomization was created by an independent statistician at the Centre for Human Drug Research using SAS software.
Intervention typeDrug
Pharmaceutical study type(s)
PhasePhase I
Drug / device / biological / vaccine name(s)Galantamine
Primary outcome measureLong-term clinical response to galantamine assed using pharmacodynamic parameters measured by the NeuroCart test battery, including:
1. The N-back tests evaluated working memory
2. Adaptive tracking measured sustained attention
3. Eye-hand coordination
4. Simple Reaction Time task measured the attention and speed of information processing
5. Visual analogue scale according to Bond and Lader assessed changes in subjective states
6. Facial encoding and recognition task episodic memory
7. Visual verbal learning test (VVLT) covered the scope of learning behaviour (i.e., acquisition, consolidation, storage and retrieval
8. Pharmaco-electroencephalography
9. Eye movements and pupil size were used to determine drug effects on neurophysiological and autonomous system function.
Pupil size, eye movements, adaptive tracking, simple reaction time, visual analogue scales and N-back tests were performed twice at baseline, and at 1, 2, 4, and 5 hours following galantamine or placebo administration. The VVLT was executed 1.5 hours after drug-administration (immediate recall) and 3.0 hours following drug-administration (delayed recall and recognition). The facial recognition task was performed at baseline and 2.5 hours after dosage. Pharmaco-EEG measurements were performed at baseline and 0,5, 1, 1,5, 2, 4 and 5 hours post galantamine administration.
Secondary outcome measures1. Pharmacokinetic parameters:
1.1 Plasma galantamine concentrations via an indwelling catheter at baseline and at 0,25, 0,5, 1, 1,5, 2, 2,5, 3,5 and 5 hours following drug administration.

2. Safety assessments by blood sampling:
2.1 Vital signs measurements
2.2 12-lead ECG
2.3 Urinalysis
2.4 Urinary drug screen
2.5 Haematology
2.6 Biochemistry
All safety assessments were performed at baseline and additionally at 0.5, 1.5 and 5.0 hours post- drug administration.

3. Clinical outcomes assessments:
3.1 The Alzheimer's Disease Assessment (ADAS)-cog subscale was used to evaluate the severity of cognitive and non-cognitive behavioral dysfunction characteristic for AD patients
3.2 Cognitive performance of subjects was assessed by the Clinical Dementia Rating Scale (CDR) in which statements related to the following 6 domains are scored: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care
3.3 The Disability Assessment in Dementia (DAD) scale was used to evaluate basic and instrumental activities of daily living (ADL)
3.4 The Mini Mental State Examination (MMSE) is a brief 30-point questionnaire test which was used to screen for cognitive impairment
3.5 With the Neuropsychiatric Inventory (NPI) diverse behavioural and psychological symptoms of dementia were measured
3.6 The ADAS-cog, CDR, DAD, MMSE and NPI were carried out after two and 6 months of treatment
Overall study start date17/06/2011
Completion date18/06/2015

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants50
Total final enrolment50
Key inclusion criteria1. Clinical diagnosis of AD
2. Mini Mental State Examination (MMSE) score ranging from 18 to 26
3. Clinical Dementia Rating (CDR) score between 0.5 and 2.0
Key exclusion criteria1. Previous or current use of CEIs, anticholinergic drugs or neuroleptics
2. Contraindications for the use of CEIs
3. Use of benzodiazepines 48 hours prior to the study days
4. History of psychiatric disorders
Date of first enrolment20/06/2011
Date of final enrolment14/10/2014

Locations

Countries of recruitment

  • Netherlands
  • Romania

Study participating centres

Centre for Human Drug Research
Zernikedreef 8
Leiden
2333 CL
Netherlands
Amsterdam UMC
De Boelelaan
Amsterdam
1081 HV
Netherlands
Spaarne Gasthuis
Boerhaavelaan 22
Haarlem
2000 AK
Netherlands
Tangent data research unit at University hospital of Bucharest
Sector 5
B-Dul Independentei Nr. 169
Bucharest
050098
Romania

Sponsor information

Centre for Human Drug Research
Research organisation

Zernikedreef 8
Leiden
2333 CL
Netherlands

Phone +31 (0) 71 5246 400
Email GGroeneveld@chdr.nl
Website http://www.chdr.nl
ROR logo "ROR" https://ror.org/044hshx49

Funders

Funder type

Research organisation

ZonMw
Private sector organisation / Other non-profit organizations
Alternative name(s)
Netherlands Organisation for Health Research and Development
Location
Netherlands

Results and Publications

Intention to publish date01/12/2019
Individual participant data (IPD) Intention to shareYes
IPD sharing plan summaryAvailable on request
Publication and dissemination planThis study is orally presented during the Neuroscience Campus Amsterdam in 2011. The interimanalysis after the challenge phase was presented at the ‘Alzheimer’s Association International Conference’ in 2013. Oral presentations were given about the results from the interim analyses on the ‘Goed Gebruik Geneesmiddelen’ conference of ZonMW in 2013 and the ‘Priority Medicine’ day of ZonMW in 2014. A manuscript is prepared for publication in Alzheimer Research and Therapy. This publication will be part of the thesis of drs. A.C. Baakman, entitled ‘Assessment of efficacy of pro-cholinergic compounds’.
IPD sharing planThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article 01/06/2022 31/10/2022 Yes No

Editorial Notes

31/10/2022: The following changes were made to the trial record:
1. Publication reference added.
2. The total final enrolment was added.
23/08/2019: Trial’s existence confirmed by Medical Ethics Committee of the VU University Medical Center