Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04701957 |
| Other study ID # |
APHP201281 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 30, 2023 |
| Est. completion date |
March 2027 |
Study information
| Verified date |
May 2024 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
LILAMAND Matthieu, MD PhD |
| Phone |
+33140054954 |
| Email |
matthieu.lilamand[@]aphp.fr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The ketogenic diet (KD) is a metabolic shift, which stimulates the liver oxidation of fatty
acids to produce ketone bodies. These ketone bodies represent an alternative fuel source for
the brain. The benefits of KD in epilepsia have been demonstrated for decades. This diet may
also provide benefits in Alzheimer's disease (AD) where neuronal glucose utilization declines
from the early stage. Besides, the KD could decrease neuroinflammation, oxidative stress and
enhance mitochondrial biogenesis. In murin models of AD, KD or Medium Chain Triglycerides
consumption were associated with lower neuroinflammation but also with a diminution of
neuropathologic features of AD (amyloid and tau lesions in the brain). Moreover, behavioural
effets and improvements in memory and motor function have been highlighted. In humans, recent
studies suggest cognitive benefits (memory, executive function) in AD, including in the Mild
Cognitive Impairment (MCI) stage. The feasibility and the adherence to the diet proved to be
correct, in small samples, in particular in MCI individuals over a short follow-up period (3
to 6 months).
This study aims at examining the feasibility of a KD followed-up for one year in participants
with early AD (N=70). Change in brain metabolism will be assessed using PET scan after 12
months, comparing KD with control diet. The effects on cognition, quality of life and daily
living functioning will be analysed. The safety, nutritional changes and adhesion to the diet
will be monitored throughout the study.
Description:
Research context:
Alongside the amyloid plaques and neurofibrillary tangles, the neuroinflammation triggered by
the central nervous system's innate immune response plays a central role in the pathogenesis
of Alzheimer's disease (AD). ß-amyloid deposition and tau lesions are accompanied by
activated microglia and astrocytes. These cells release proinflammatory cytokines and
chemokines causing chronic neuroinflammation. In turn, neuroinflammation promotes
neurodegeneration and ß-amyloid production. Many relationships have been demonstrated not
only between glucose metabolism and neuroinflammation, but also between glucose metabolism
and AD. Hyperglycemia promotes neuroinflammation leading to oxydative stress and
neurodegeneration. Insulinoresistance (e.g. in type 2 diabetes) or low IGF-1 levels are
associated with increased ß-amyloid production. In the absence of glucose, the brain may use
another fuel: ketogenic bodies (KB) produced by oxydation of fatty acids. The ketogenic diet
(KD) (defined by low carbohydrate intake (< 10%) in AD animal models led to a slower
cognitive decline, decreased neuroinflammation and amyloid and tau deposition. In humans, the
KD is safe and is an efficient validated treatment of drug-resistant epilepsy to decrease the
number of seizures and to improve the cognitive development in epileptic children. In AD,
although KD is publicized within the community, evidence-based data regarding efficiency is
scarce.
State of art and preliminary observations: Preclinical studies: - Ketone bodies may play a
neuroprotective effect against beta-amyloid toxicity. In cultured hippocampal neurons of
rats, the direct application of the ketone ß-hydroxybutyrate in relevant concentrations
protects hippocampal neurons from beta-amyloid toxicity. The addition of ß-hydroxybutyrate
however, reversed Aß toxicity, acting instead as a growth factor that doubled the number of
surviving cells. - In 3xTgAD mice, a ketogenic diet suppressed beta-amyloid and tau pathology
in the brain; the ketogenic-fed mice also experienced superior cognitive perfomance compared
with control: improved memory. Likewise, in another model of AD (APP/V717I young mice), a KD
vs control diet was associated with lower amyloid levels. - Several other animal studies have
highlighted the potential clinical benefits of KD: improved visuo-spatial function in aged
dogs, improved motor function in amyloid and tau models of mice, in APP/PS1 knock-in mice, or
in old rats.
Human studies - A clinical trial specifically assessed the feasability of a very high-fat
ketogenic diet in participants with AD, with a 3- month follow-up. This diet proved feasible
in CDR 0,5 and CDR 1 participants. Moreover, all the participants but one adapted to the diet
and achieved ketosis. Study completers showed significant cognitive improvement on the
ADAScog scale. - A couple of studies have examined the impact of KD or MCT supplementation in
participants affected by mild-tomoderate AD. Four of them suggested clinical benefits in
terms of short-term memory or visuo-spatial function, especially in those who did not have
any APOE-e4 allele. Nevertheless all these studies included small samples of participants (N
< 50) and / or short follow-up (< 3 months). - Recently a ketogenic drink showed promising
results in terms of brain energy and cognition in MCI subjects. A similar nutritional
intervention, in individuals with AD, was associated with improvements in cerebral blood flow
using PET imaging after 45 days.
Methods:
Randomized controlled trial conducted in one memory center in Paris Region
(Laribosière-Fernand Widal). All the participants will be included after diagnosis of AD
based on comprehensive neuropsychological and clinical assessments, brain 3-Tesla MRI, FDG
TEP scanner and CSF biomarkers.
Trial overview:
- After signing the informed consent, the participants (N=70) will be randomly assigned
either to the intervention group (i.e. ketogenic diet modified Atkins 2:1) or to the
control group (i.e. normal diet + nutritional advice)
- Follow-up = 12 months with 3 clinicat visits: baseline, 6 and 12 months
- 6 dietitian consultations in both groups (day 1, day 15, month 1, month 3, month 5,
month 9)
- All the visits comprise:
- ketosis measure using urinary strips
- cognitive assessment: MMSE, CDR
- daily functioning assessment: ADSC-ADL-Pi
- quality of life assessment: SF-36
- After 12 months, the participants will undergo another brain FDG PET scanner to assess
change in brain metabolism. All the PET analyses will be performed by nuclear medicine
physicians blinded from randomization group.
- Justification of sample size:
A sample size of N= 35 patients per group will allow an estimate of any adherence to KD
larger or equal to 75% with a precision of at least ± 15%. In addition it will allow to
estimate the mean values of the main clinical and biological endpoints of interest with a
precision equal to 35% of their SD , that will allow to optimize the design and sample size
calculation for a next larger RCT on this topic.
- Adherence to diet and potential adverse effects will be monitored throughout the study.
Ketosis achievement and ketonuria related to KD will be confirmed using urinary tests.
- All the participants will be provided instructions by one study dietitians, at the 3
visits and in 3 additional consultations. Individuals from the intervention group will
be given food lists and specific recommandations about ketogenic food. Nutritional
advice from the National French Nutrition Programme will be given to the participants of
the control group
- The study protocol will be written with our Clinical Research Unit and approved by the
French Ethics Committee (Comité de Protection des Personnes)
