Comparison of Therapeutic Strategies With Cholinesterase Inhibitors (SOS TRIAL)

Summary

Cholinesterase inhibitors (CI) remain the only drugs with a recognized efficacy in mild to moderate Alzheimer's disease (AD) in spite of enormous research efforts. However, these drugs presented as "symptomatic treatment" of AD are considered as having only a weak effect on the course of AD. The reimbursement of these drugs is regularly challenged due to the lack of evidence for the impact of these drugs on milestones stages of AD evolution (survival without severe dementia, restriction in Basic Activities of Daily Living - BADL) and on major consequences in public health (hospitalization and institutionalization). The great majority of previous randomized controlled trials conducted with CI have had a too short duration and the end points were limited to cognition (ADAS Cog scale), IADL (Instrumental Activities of Daily Living) function and Global Impression of Change. New evidences from the DOMINO trial (1) conducted in UK, independently of the pharmaceutical industry, showed that the true effect of CI might be more to avoid or to delay the cognitive or functional decline in AD than to improve patients; the institutionalisation (2) was also delayed. However, this trial was conducted in patients with moderate to severe AD, and the interest of the drugs at the mild to moderate stage remains questionable. The investigators have shown that a good surrogate marker of survival without severe dementia would be an increase of ADAS Cog scale of more than six points (3). A post hoc reanalysis of the pivotal RCT with two CI showed that in mild to moderate patients, CI was associated with a 15% decrease of patients with a deterioration of ADAS-Cog of more than six points in six months. Thus at the beginning of dementia the real effect of CI might be more of delaying the cognitive and functional decline, than to improve the patients. The main objective of the SOS trial is to demonstrate that the benefit of CI at the early phase of dementia is the same as at the later phase.

Interventions

• cholinesterase inhibitors (CI) (donepezil, galantamine or rivastigmine) · DRUG

  The choice of the treatment will be done by the specialist according to his habits; the specialist will monitor the treatment as usual. All the recruited patients will be treated by CI according to the recommendations of the French HAS and the clinician's habits to choose the type of CI and adjust the dosage. After a 6-month period under CI treatment, patients will be classified according to the evolution of the Mini Mental State Examination (MMSE) as "non-responders" or responders. Responders patients will continue their treatment according to the habits of the clinician. Non-responder patients will be included in the RCT, with individual randomization in two groups: one group who stops the CI, one group who continues the CI. All randomized patients will then be followed-up for two years with regular assessment of judgment criteria every 6 months.

Published eligibility criteria

Verbatim from the registry. Only the site can decide how these apply to a specific patient.

Inclusion Criteria:

* New case of AD referring to a CMRR or MC.
* Diagnosis of probable or possible AD, defined according to the NINCDS-ARDRA criteria
* Mild to moderate stage, defined by a MMSE score above 15 at the time of pre-inclusion
* Patients with indication to CI treatment
* Patients Naïve to CI treatment
* Patients aged 50 years or more
* Menopause or effective contraception (for women)
* Affiliated person or beneficiary of a social security scheme
* Patients with AD LTI (Long Term Illeness)
* Patients agree to participate, with free, informed and written consent signed by the patient and his caregiver

Non Inclusion Criteria:

* Patients diagnosed with Lewy bodies disease, fronto-temporal dementia, or dementia from a cause other than Alzheimer Disease
* More severe stage of the disease, defined by a MMSE equal or below 15 at the time of inclusion
* Patients with contraindication to CI treatment
* Patients residing in an institution at the time of pré-inclusion or randomization
* Patients with a complete dependency for bathing and dressing at the time of pré-inclusion or randomization ( ADL de Katz, score 2/2 for the item "bathing" and/or "dressing")
* Patients under tutorship or curatorship, patients unable to express consent
* Patients with unstable severe general disease compromising the follow-up
* Patients without caregiver
* Patients included in another pharmacological trial
* Pregnant or breastfeeding women

Exclusion Criteria:

* CI responder patients for whom the MMSE score remained stable or became higher after 6 months of treatment
* Patients with complete dependency for bathing and dressing at the randomization visit
* Patients residing in an institution at the randomization visit

Sites (31)

• CHU d'Amiens Centre Mémoire Ressources Recherche, Amiens, France
• CHU d'Angers Centre Mémoire Ressources Recherche, Angers, France
• CHU de Bastia Centre Mémoire Ressources Recherche, Bastia, France
• CHU de Besançon Centre Mémoire Ressources Recherche, Besançon, France
• CHU de Bordeaux - Service de Neurologie - Centre Mémoire Ressources Recherche -, Bordeaux, France
• CHRU Cavale Blanche Service de Gériatrie, Brest, France
• Service de Neuropsychologie Hôpital Neurologique Pierre Wertheimer, Bron, France
• CHU Côte de Nacre Service de neurologie et CMRR, Caen, France
• CHU de Clermont Ferrand Centre Mémoire Ressources Recherche, Clermont-Ferrand, France
• Hôpital Pasteur Service de Neurologie, Colmar, France
• CHU de Dijon- CMRR, Dijon, France
• Chu de Grenoble CMRR, Neurologie, Grenoble, France
• Hôpital Roger Salengro CMRR, Lille, France
• CHU Limoges Service de neurologie et CMRR, Limoges, France
• AP-HM, Marseille, France
• CHU Montpellier Hôpital Gui de Chauliac CMRR, Montpellier, France
• CHU de Nantes Clinique Neurologique Hôpital GR Laennec, Nantes, France
• Institut Claude Pompidou Centre Mémoire de Ressources et de Recherche, Nice, France
• APHP Hôpital Broca, Paris, France
• Hôpital Universitaire de la Pitié Salpêtrière Pavillon François Lhermitte, Paris, France
• APHP Groupe Hospitalier Saint Louis Lariboisière Fernand Widal CMRR, Paris, France
• CHU La Milétrie Pôle de Gériatrie, Poitiers, France
• CHU Reims Hôpital Maison Blanche Court Séjour Gériatrique, Reims, France
• CHU de Rennes - Hôpital Pontchaillou / Service de Neurologie, Rennes, France
• CHU de Rouen Hôpital Charles Nicolle Service Neurologie, Rouen, France
• Chu de Saint-Etienne, CMRR, Saint-Etienne, France
• Chu de Strasbourg Hôpital Ka Robertsau Pôle de Gériatrie - CMRR, Strasbourg, France
• Centre de Recherche Clinique du Gérontopôle Cité de la Santé, Toulouse, France
• CHRU de Bretonneau Unité de gérontopsychiatrie, Tours, France
• CHU Nancy Service de Gériatrie-CMRR, Vandœuvre-lès-Nancy, France
• Hospice Civil de Lyon Hôpital des Charpennes, Villeurbanne, France