Efficacy and Tolerability of Memantine in Frontotemporal Dementia (FTD) Patients

• ClinicalTrials.gov Identifier: NCT00200538
• Recruitment Status: Completed
• First Posted: September 20, 2005
• Last Update Posted: May 3, 2013
• Sponsor: Nantes University Hospital
• Information provided by: Nantes University Hospital

Tracking Information

• First Submitted Date: September 12, 2005
• First Posted Date: September 20, 2005
• Last Update Posted Date: May 3, 2013
• Study Start Date: September 2005
• Primary Completion Date: Not Provided
• Current Primary Outcome Measures: Not Provided
• Original Primary Outcome Measures: Not Provided
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Tolerability of Memantine in Frontotemporal Dementia (FTD) Patients
• Official Title: Double-blind, Parallel Group, Placebo-controlled Trial of the Efficacy and Tolerability of Memantine (20 mg) in Frontotemporal Dementia (FTD) Patients
• Brief Summary: The purpose of this trial is to assess the efficacy and tolerability of memantine (anti-excitotoxic, neuroprotective treatment currently used in Alzheimer's disease [AD]) in frontotemporal dementia patients after a one-year treatment.

Detailed Description

Background: Frontotemporal dementia (FTD) is the first cause of dementia in the presenium (onset before the age of 65 years). Characterized by behavioral disorders, it is often more incapacitating than Alzheimer's disease (AD), and leads to death within 7 years on average (9-10 years for AD). It affects young individuals (on average, 20 years younger than in AD), who are often still active. Management of these patients is therefore burdensome and complex. As opposed to AD, however, no treatment is currently available. Few therapeutic trials have actually been conducted on this disorder. Many reasons may account for this:

1. recent availability of reliable diagnostic criteria (the Lund and Manchester groups' consensus statement in 1994; revised in 1998),
2. the very small number of cases as opposed to AD-the number of cases was estimated at approximately 3,500 vs 600,000, for AD, in France in 2004-, FTD therefore falls into the category of rare diseases (i.e., less than 30,000 cases),
3. the scarcity of valuable physiopathological hypotheses.

Besides a non-specific serotoninergic dysfunction, no significant anomalies related to particular neuromediators have apparently been found (as opposed to AD, which is characterized by a cholinergic deficit). In 1998, the discovery of mutations in the Tau gene in certain kindreds showing a dominant autosomal transmission of FTD, oriented research efforts toward the tau protein and provided new perspectives. Many studies have suggested the role of excitotoxicity. Abnormal aggregation of the tau protein has been observed in the brains of a majority of FTD patients (familial and sporadic form). Excitotoxicity may be responsible for promoting this abnormal aggregation through modification of the expression and phosphorylation state of the tau protein. The hypothesis of this study is that an anti-excitotoxic neuroprotective treatment may slow the pathogenic process and therefore be an effective treatment for this pathology.

Goals: To assess the efficacy and tolerability of memantine (anti-excitotoxic, neuroprotective treatment currently used in AD) in FTD patients after a one-year treatment.

Type of study: National, multicenter, randomized, double-blind, parallel group, placebo-controlled, phase II therapeutic trial.

Study design: Sixty four (64) patients, aged 45 to 75 years, will be enrolled in the study for a period of 12 months (clinical inclusion criteria are defined based on the Lund and Manchester group consensus statement [revised version 1998]), and followed up for 1 year in a controlled study. At the time of inclusion, the Mini Mental Status Examination (MMSE) score should be at least 19 (below 18, a neuropsychological examination is impossible). Patients will either take memantine, or a placebo (randomization ratio of 1:1) twice a day (i.e., 20 mg of memantine per day in the memantine arm). The primary efficacy variable will be a global assessment tool, the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). Secondary efficacy variables will include behavioral scales [the NeuroPsychiatric Inventory (NPI), the Frontal Behavior Inventory (FBI)], cognitive scales [the Mattis Dementia Rating Scale (MDRS), the MMSE], activities of daily living (Disability Assessment for Dementia, DAD), time spent by the caregiver of the patient (Resource Utilization in Dementia, RUD), and caregiver burden scale (Zarit Burden Inventory), and tolerability of the drug. The main analysis will be carried out on an intention-to-treat basis in all randomized patients having undergone at least one evaluation after inclusion (the Last Observation Carried Forward LOCF value, will be attributed to missing values). This analysis will be carried out at the end of the double-blind study (main judgement criterion)

Expected results and perspectives: The main expected result is the confirmation of the efficacy of memantine as a treatment for FTD, which would set a precedent in the treatment of this disease. Such a result could also lead the way to the development of treatments for other related neurodegenerative disorders (tauopathies) such as the other frontotemporal lobar degenerations (semantic dementia, progressive non-fluent aphasia), progressive supranuclear palsy, or corticobasal degeneration. Finally, the standardized follow-up of a 64 patient cohort in this study will provide important information on the natural history of a rare and poorly-known disease.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Dementia
• Intervention: Drug: memantine
• Study Arms: Not Provided

Publications *

• Boutoleau-Bretonniere C, Lebouvier T, Volteau C, Jaulin P, Lacomblez L, Damier P, Thomas-Anterion C, Vercelletto M. Prospective evaluation of behavioral scales in the behavioral variant of frontotemporal dementia. Dement Geriatr Cogn Disord. 2012;34(2):75-82. doi: 10.1159/000341784. Epub 2012 Aug 23.
• Vercelletto M, Boutoleau-Bretonniere C, Volteau C, Puel M, Auriacombe S, Sarazin M, Michel BF, Couratier P, Thomas-Anterion C, Verpillat P, Gabelle A, Golfier V, Cerato E, Lacomblez L; French research network on Frontotemporal dementia. Memantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis. 2011;23(4):749-59. doi: 10.3233/JAD-2010-101632.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 2, 2013): 52
• Original Enrollment (submitted: September 12, 2005): 64
• Study Completion Date: Not Provided
• Primary Completion Date: Not Provided

Eligibility Criteria

Inclusion Criteria:

• Patients with FTD based on the criteria defined by the Lund and Manchester groups' consensus statement (revised in 1998), whose disease has been progressing during the last year.
• MMSE score of 19 or higher
• Men and women aged 45 to 75 years
• Without speech, visuospatial, or episodic memory impairments

Exclusion Criteria:

• Age > 76 years
• Illiterate or misunderstanding patients
• Patients with cancer, heart disease, lung disease, kidney disease (creatinine > 200 mg/dL), or epilepsy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 45 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT00200538
• Other Study ID Numbers: BRD 05/1-E
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Not Provided
• Original Responsible Party: Same as current
• Current Study Sponsor: Nantes University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Martine Vercelletto, MD; Centre de la Mémoire, Clinique Neurologique CHU Nord Nantes 44093 France; mvercelletto@chu-nantes.fr
• Principal Investigator: Lucette Lacomblez, MD; Federation de Neurologie AP-HP Paris 75 013 France; lucette.lacomblez@psl.ap-hop-paris.fr
• Principal Investigator: Bruno Dubois, MD; Centre du Langage et de Neuropsychologie AP-HP Paris 75013 France; b.dubois@psl.ap-hop-paris.fr
• Principal Investigator: Anne Sophie Rigaud, MD; Hôpital Broca, Paris 75 France; anne-sophie.rigaud@brc.ap-hop-paris.fr
• Principal Investigator: Jean-Francois Dartigues, MD; Hôpital Pellegrin Bordeaux 33 076 France; jean-francois.dartigues@u.bordeaux2.fr
• Principal Investigator: Sophie Auriacombe, MD; Hôpital Pellegrin Bordeaux 33 076 France ; sophie.auriacombe@u.bordeaux.fr
• Principal Investigator: Philippe Couratier, MD; Hôpital Dupuytren, Limoges 87000 France; philippe.couratier@unilim.fr
• Principal Investigator: Jacques Touchon, MD; Hôpital Gui de Chaulliac, Montpellier 34 295 France; jacques.touchon@wanadoo.fr
• Principal Investigator: Matthieu Ceccaldi, MD; Hôpital de la Timone Marseille 13 005 France; mceccaldi@ap-hm.fr
• Principal Investigator: Mira Didic, MD; Hôpital de la Timone Marseille 13005 France; mira.didic@medecine.univ-mrs.fr
• Principal Investigator: Serge Bakchine, MD; Hôpital Maison Blanche, Reims 51 092 France; sbakchine@chu-reims.fr
• Principal Investigator: Bernard-Francois Michel, MD; Hôpital Sainte Marguerite, 13009 France; bmichel@ap-hm.fr
• Principal Investigator: Catherine Thomas-Anterion, MD; Hôpital Bellevue Saint Etienne, 42 000 France; catherine.thomas@chu-st-etienne.fr
• Principal Investigator: Bernard Laurent, MD; Hôpital Bellevue Saint Etienne 42 000 France; bernard.laurent@univ-st-etienne.fr
• Principal Investigator: Francois Sellal, MD; Hôpital Civil Strasbourg 67000 France; francois.sellal@chru-strasbourg.fr
• Principal Investigator: Serge Belliard, MD; Hôpital Pontchaillou Rennes 35 000, France; serge.belliard@chu-rennes.fr
• Principal Investigator: Herve Allain, MD; Service de Pharmacologie, CHU de Rennes 35 000 France ; Herve.allain@univ-rennes1.fr
• Principal Investigator: Michele Puel, MD; Hôpital Purpan, Toulouse 31059 France; PUEL.M@chu-toulouse.fr
• Principal Investigator: Jean-Francois Demonet, MD; Clinique Neurologique CHU Purpan Toulouse 31059 France; demonet@toulouse.inserm.fr
• Principal Investigator: Marie Sarazin, MD; Centre du Langage et de la Mémoire, Hôpital de la Salpétriére AP-HP Paris 75013 France

• PRS Account: Nantes University Hospital
• Verification Date: January 2005