Multicenter randomized, double-blind, placebo controlled trial evaluating the effect of a 30-week caffeine treatment on cognition in early-to moderate Alzheimer's disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Lille

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

31 Oct 2024 → ongoing

Decision date (initial)

2024-10-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Meo Fichaux · GIRCI Nord-Ouest · Laboratoire d'excellence DISTALZ · Conseil régional Hauts-de-France

External identifiers

EU CT number

2024-514099-41-00

EudraCT number

2019-002360-27

ClinicalTrials.gov

NCT04570085

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Evaluate the caffeine efficacy (30 weeks of treatment) compared to placebo on cognitive decline in beginning to moderate stage Alzheimer's disease dementia (16 ≤ MMSE ≤ 26)

Secondary objectives 4

1. To evaluate the effect of 30 weeks caffeine treatment compared to placebo and to evaluate the persistent effect of caffeine treatment 6 weeks after discontinuation (visit V6: 36 weeks after randomization): • On cognitive and attentional functions • On functional autonomy • On the life quality / the impression of change • The caregiver burden
2. To evaluate the heterogeneity of the 30-week caffeine treatment effect according to the following pre-defined subgroups: iAChE treatment (yes/ no), APOE4 genotype (homo / hetero / null), caffeine metabolism (slow / fast) and gender (male / female)
3. To evaluate the effect of 30 weeks caffeine treatment compared to placebo on the adverse effects occurrence
4. To evaluate the effect of 30 weeks caffeine treatment compared to placebo on the caffeine increase and its three dimethylated metabolites (paraxanthine, theophylline, theobromine) in the morning on an empty stomach

Conditions and MedDRA coding

Alzheimer's disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Men and / or women
2. Age> 50 at inclusion
3. Dementia related to probable Alzheimer's disease according to the criteria of the National Institute on Aging-Alzheimer's Association; the diagnosis must be supported by brain imaging (CT or MRI) and a blood test (including ionogram, renal and hepatic function, calcemia, CRP, TSH, B12 vitamins and folate) performed in routine care
4. MMSE score between 16 and 26 (terminals included)
5. Presence of a partner informing and helping> 10h / week
6. If the participant is being treated with acetylcholine esterase inhibitors (AChEIs) and/or memantine, the treatment must be at an effective and stable dose for 2 months prior to the screening visit and must remain stable for the duration of the study
7. Patient giving written consent
8. Social insured patient
9. Patient willing to comply with all procedures of the study and its duration

Exclusion criteria 15

1. Patients refusing to adopt a diet low in caffeine (eviction of tea, caffeinated sodas, chocolate in large quantities)
2. Current major depressive episode according to DSM-5 criteria
3. Other chronic pathology of the central nervous system
4. Major anxiety according to the clinician (in coherence with the corresponding NPI-R items which must indicate a gravity> 2 and a repercussion> 3)
5. Sleep disorders defined by gravity> 2 and a repercussion> 3 on the NPI-R; a patient paired for OSAS may be included if the equipment has been in use for> 3 months and is well tolerated (stable)
6. Decompensated heart disease or severe rhythm disorder (excluding slow, treated and stable chronic atrial fibrillation)
7. Any significant comorbidity that may be confounding by the clinician
8. Active smoking
9. Excessive alcohol consumption (> 3 units per day on average)
10. Behavioral disorders incompatible with neuropsychological assessment
11. Participation in an interventional therapeutic trial
12. Non native French-speaking patient or illiterate.
13. For women of childbearing age: pregnancy in progress or planned (A pregnancy test will be performed)
14. Patients taking prohibited treatment: - Psychotropic treatments (antidepressants, euroleptics, anxiolytics, hypnotics and mood regulators) introduced or modified <2 months before inclusion - Chronic intake of drugs inducing or inhibiting CYP1A2 - Inhibitory drugs: Artemisinin, Atazanavir, Cimetidine, Ciprofloxacin, Enoxacin, Ethinyl Estradiol, Fluvoxamine, Mexiletine, Thiabendazole, Norfloxacine, Stiripentol - Inducing drugs: Barbiturates, Carbamazepine, Primidone, Rifampicin - All specialties containing caffeine: ACTRON®, ALEPSAL®, ALGODOL CAFEINE®, ANTIGRIPPINE A®, ASPRO CAFEINE®, CEFALINE HAUTH®, COOPER® COFFEE CITRATE, CLARADOL CAFEINE®, GCFORM®, GURONSAN®, GYNERGENE CAFEINE® , LAMALINE®, MERCALM®, METASPIRINE®, PARACETAMOL / CAFEIN / CODEINE MYLAN®, PERCUTAFEINE®, PRONTALGINE® - Drugs that influence the metabolism of caffeine (after 2): quinolones, antiarrhythmics (Mexiletine, Diltiazem, Verapamil), fluvoxamine (antidepressant), omeprazole (proton pump inhibitor), Furafylline and Theophylline (bronchodilators) - Drugs likely to interact with caffeine: in the class of anti-epileptics: Carbamazepine, Diazepam, Phenytoin, Ethosuximide, Valproate, Gabapentin, Topiramate, Lithium
15. CAFCA-MRI and CAFCA-TEP ancillary studies: Patients with a contraindication for MRI and / or PET scans

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Variation in total NTB score (z-score) at 30 weeks post-randomization (difference between randomized value and value after 30 weeks of treatment)

Secondary endpoints 5

1. For evaluation of the effect of caffeine compared to placebo 30 weeks after randomization 1.1) On cognitive functions, variation between baseline (randomization) and V5 (30 weeks after randomization) of the following parameters: - MMSE score - NTB executive functions sub-score - NTB memory sub-score o Simple reaction time to TAP test - Complex reaction time in the TAP test o Epworth score 1.2) Functional autonomy, variation between the baseline and V4 (30 weeks after randomisation) of the DAD
2. To evaluate the persistent effect of caffeine treatment 6 weeks after its interruption (visit V5, 36 weeks after randomisation): variation of the previous parameters (except the CGIC score) between the baseline and V5 ; CGIC score at V5
3. Heterogeneity of the effect of caffeine treatment On the following pre-defined subgroups: iAChE treatment (yes / no), APOE4 genotype (homo / hetero / null), caffeine metabolism (slow / fast) and gender (male / female); the variation of the NTB score (main criterion) between the baseline and the V4 visit.
4. Evaluate the effect of caffeine compared to placebo on the occurrence of adverse events during follow-up (from randomization to visit V5) Evolution during follow-up of NPI scores, NPI-R sleep, NPI-R anxiety, heart rate, blood pressure.
5. Evaluate the effect of caffeine compared to placebo on the increase of caffeine and its three dimethylated metabolites (paraxanthine, theophylline, theobromine) in the morning on an empty stomach Evolution during the monitoring of the value of caffeine and the concentration of its three dimethylated metabolites (paraxanthine, theophylline, theobromine) in the morning on an empty stomach.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Lille

Sponsor organisation

Centre Hospitalier Universitaire De Lille

Address

2 Avenue Oscar Lambret, Cs 70001 Cs 70001

City

Lille Cedex

Postcode

59037

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Thibaud Lebouvier

Public contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Mme Brigitte COURTOIS

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications