Comparison of Therapeutic Strategies With Cholinesterase Inhibitors (SOS TRIAL)

Official title

Comparison of Therapeutic Strategies With Cholinesterase Inhibitors: Stop or Still (SOS) Trial

Overview

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

• Drug cholinesterase inhibitors (CI) (donepezil, galantamine or rivastigmine)
  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

Primary outcome measures

• The primary outcome is a combination of complete BADL dependency in bathing and dressing and/or institutionalization or death at 2 years after randomization. [Time frame: at 30 months after patient's inclusion]

Secondary outcome measures (12)

• BADL dependency will be evaluated by the clinician using the BADL scale from Katz [17]. [Time frame: at inclusion]
• BADL dependency will be evaluated by the clinician using the BADL scale from Katz [17]. [Time frame: at 6 months]
• BADL dependency will be evaluated by the clinician using the BADL scale from Katz [17]. [Time frame: at 12 months]
• BADL dependency will be evaluated by the clinician using the BADL scale from Katz [17]. [Time frame: at 18 months]
• BADL dependency will be evaluated by the clinician using the BADL scale from Katz [17]. [Time frame: at 24 months]
• BADL dependency will be evaluated by the clinician using the BADL scale from Katz [17]. [Time frame: at 30 months]
• Combination of complete BADL dependency in bathing and dressing and/or institutionalization or death [Time frame: at inclusion]
• Combination of complete BADL dependency in bathing and dressing and/or institutionalization or death [Time frame: at 6 months]
• Combination of complete BADL dependency in bathing and dressing and/or institutionalization or death [Time frame: at 12 months]
• Combination of complete BADL dependency in bathing and dressing and/or institutionalization or death [Time frame: at 18 months]
• Combination of complete BADL dependency in bathing and dressing and/or institutionalization or death [Time frame: at 24 months]
• Combination of complete BADL dependency in bathing and dressing and/or institutionalization or death [Time frame: at 30 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 31 centers

• CHU d'Amiens Centre Mémoire Ressources Recherche — Amiens
• CHU d'Angers Centre Mémoire Ressources Recherche — Angers
• CHU de Bastia Centre Mémoire Ressources Recherche — Bastia
• CHU de Besançon Centre Mémoire Ressources Recherche — Besançon
• CHU de Bordeaux - Service de Neurologie - Centre Mémoire Ressources Recherche - — Bordeaux
• CHRU Cavale Blanche Service de Gériatrie — Brest
• Service de Neuropsychologie Hôpital Neurologique Pierre Wertheimer — Bron
• CHU Côte de Nacre Service de neurologie et CMRR — Caen
• … and 23 more centers

Identifiers

NCT: NCT03454646 · CHUBX 2016/27

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗