Memantine (10mg BID) for the Frontal and Temporal Subtypes of Frontotemporal Dementia

Semantic Dementia Clinical Trial

Official title:

A Prospective, Randomized, Multi-Center, Double-Blind, 26 Week, Placebo-Controlled Trial of Memantine (10mg BID) for the Frontal and Temporal Subtypes of Frontotemporal Dementia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00545974
• Other study ID #: NAM-53:memantineplacebo
• Status: Completed
• Phase: Phase 4
• Start date: October 2007
• Est. completion date: December 2012

Study information

• Verified date: October 2020
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the study is to determine whether memantine is effective in slowing the rate of behavioral decline in frontotemporal dementia. The secondary objective of the study is to assess the safety and tolerability of long-term treatment with memantine in patients with frontotemporal dementia (FTD) or semantic dementia (SD). To determine whether memantine is effective in slowing the rate of cognitive decline in frontotemporal dementia. To evaluate whether memantine delays or decreases the emergence of parkinsonism in frontotemporal dementia. The tertiary objective of the study is to determine whether treatment with memantine affects changes in weight

Description:

This is a multicenter, randomized, double-blind, placebo-controlled trial of memantine 10 mg twice daily versus placebo, at a ratio of 1:1, to receive active drug or placebo. Screening and enrollment is planned to last approximately one year. A Data and Safety Monitoring Board, consisting of a clinical pharmacist and 3 neurologists will review all AE reports approximately every 3 months after study initiation. The DSMB will notify the principal investigator, the study sponsor and the CHR if significant concerns are raised by their review of the AE data. An interim analysis of efficacy data will be conducted after 50% of the targeted enrollment population has completed 26 weeks of drug treatment. Including screening and off-drug follow up, each subject will participate in the study for approximately 34 weeks. The entire study is anticipated to last 86 weeks if enrollment is completed within one year of study initiation. The targeted enrollment is 140.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 81
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

A subject must meet ALL of the following criteria to be considered for enrollment in this

study:

1. Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations.

2. Must meet criteria Neary et al. criteria for frontotemporal dementia (FTD) or semantic dementia (SD)

3. Age: 40-80

4. CT or MRI of brain within 12 months consistent with a diagnosis of FTD or SD.

5. MMSE = 15 at screening visit.

6. Judged by investigator to be able to comply with neuropsychological evaluation at baseline.

7. Must have reliable caregiver accompany subject to all study visits. Caregiver must read, understand and speak English fluently in order to ensure comprehension of informed consent form and informant-based assessments of subject. Caregiver must also have frequent contact with subject (at least 3 times per week for one hour) and be willing to monitor study medication compliance and the subject's health and concomitant medications throughout the study.

8. In the opinion of the investigator, the patient and the caregiver will be compliant with the protocol and have a high probability of completing the study. Exclusion Criteria:

Any one of the following will exclude a subject from being enrolled into the study:

1. Insufficient fluency in English to complete neuropsychological and functional assessments.

2. Concurrent Motor Neuron Disease judged by investigator to have bulbar or upper extremity impairments at baseline that would interfere with neuropsychological assessment, or that are expected to lead to such impairments within one month.

3. Exclusion criteria as listed in Neary criteria. Diagnosis of progressive nonfluent aphasia by Neary criteria.

4. Use of memantine within 4 weeks prior to randomization.

5. Evidence of other neurological or psychiatric disorders which preclude diagnosis of FTD (including, but not limited to, stroke, Parkinson's disease, any psychotic disorder, severe bipolar or unipolar depression, seizure disorder, or head injury with loss of consciousness) within the past year.

6. Concurrent treatment with acetylcholinesterase inhibitors, antipsychotic agents, mood stabilizers (valproate or lithium) or benzodiazepines (other than temazepam or zolpidem), or use of any of these agents within 4 weeks prior to randomization. Atypical antipsychotic agents may be started after the baseline visit if felt to be medically necessary by the investigator and will be recorded as a secondary outcome measure.

7. History of alcohol or substance abuse within 1 year prior to screening, if deemed clinically significant by investigator.

8. Any current malignancy, or any clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal or neurological disease. If the condition has been stable for at least the past year and is judged by the investigator not to interfere with the patient's participation in the study, the patient may be included.

9. Clinically significant lab abnormalities at screening, including Creatinine = 1.7, B12 below laboratory normal reference range or TSH above site's laboratory normal reference range. Subjects with abnormal B12 or TSH levels at screening may be included per investigator's discretion.

9. CT or MRI evidence of any of the following: hydrocephalus, stroke, space-occupying lesion, cerebral infection or any clinically significant CNS disease other than FTD. 10.Systolic blood pressure greater than 180 or less than 90 mm Hg. Diastolic blood pressure greater than 105 or less than 50 mm Hg.

11. Abnormal ECG at screening judged to be clinically significant by the investigator.

12. Use of investigational drugs or participation in investigational drug study within 60 days of screening.

Related Conditions & MeSH terms

• Alzheimer Disease
• Aphasia, Primary Progressive
• Dementia
• Frontal Lobe Dementia
• Frontotemporal Dementia
• Frontotemporal Lobe Dementia
• Pick Disease of the Brain
• Semantic Dementia

Intervention

Drug:
• memantine
memantine 10mg BID
• Placebo pill
Placebo pill BID

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University Hospitals of Cleveland / Case Medical Center	Cleveland	Ohio
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of California, Los Angeles	Los Angeles	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University California, San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	Forest Laboratories

Country where clinical trial is conducted

United States, 

References & Publications (27)

Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, Canu N. NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2892-7. Epub 2006 Feb 13. — View Citation

Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf-Radford N, Mendez M, Kerwin D, Lerner A, Wu CK, Koestler M, Shapira J, Sullivan K, Klepac K, Lipowski K, Ullah J, Fields S, Kramer JH, Merrilees J, Neuhaus J, Mesulam MM, Miller BL. Memantine in — View Citation

Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005 Oct-Dec;19 Suppl 1:S3-6. Review. — View Citation

Boxer AL, Trojanowski JQ, Lee VY-M, Miller BL (2005) Frontotemporal Lobar Degeneration. In: Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics (Beal MF, Lang AE, Ludolph AC, eds), pp 481 - 493. Cambridge, UK: Cambridge University Press.

Cullum CM, Saine K, Chan LD, Martin-Cook K, Gray KF, Weiner MF. Performance-Based instrument to assess functional capacity in dementia: The Texas Functional Living Scale. Neuropsychiatry Neuropsychol Behav Neurol. 2001 Apr-Jun;14(2):103-8. — View Citation

Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997 May;48(5 Suppl 6):S10-6. Review. — View Citation

Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. — View Citation

Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee VM, Miller BL, Trojanowski JQ, Grossman M. Frontotemporal dementia: clinicopathological correlations. Ann Neurol. 2006 Jun;59(6):952-62. — View Citation

Huey ED, Putnam KT, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology. 2006 Jan 10;66(1):17-22. Review. — View Citation

Josephs KA, Duffy JR, Strand EA, Whitwell JL, Layton KF, Parisi JE, Hauser MF, Witte RJ, Boeve BF, Knopman DS, Dickson DW, Jack CR Jr, Petersen RC. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain. 2006 Jun;129(Pt 6):1385-98. Epub 2006 Apr 13. — View Citation

Josephs KA, Petersen RC, Knopman DS, Boeve BF, Whitwell JL, Duffy JR, Parisi JE, Dickson DW. Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology. 2006 Jan 10;66(1):41-8. — View Citation

Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J Neurol Sci. 1997 Feb;24(1):29-36. — View Citation

Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain. 2005 Sep;128(Pt 9):1996-2005. Epub 2005 Jul 20. — View Citation

Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994 Mar 3;330(9):613-22. Review. — View Citation

Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006 Feb;5(2):160-70. Review. — View Citation

Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry. 2007 Jan;15(1):84-7. — View Citation

Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging. 2004;21(14):931-7. — View Citation

Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. — View Citation

Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998 Dec;51(6):1546-54. Review. — View Citation

Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002 Jul;33(7):1834-9. — View Citation

Pijnenburg YA, Sampson EL, Harvey RJ, Fox NC, Rossor MN. Vulnerability to neuroleptic side effects in frontotemporal lobar degeneration. Int J Geriatr Psychiatry. 2003 Jan;18(1):67-72. — View Citation

Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ; Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003 Apr 3;348(14):1333-41. — View Citation

Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. — View Citation

Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc. 1992 Dec;40(12):1221-6. — View Citation

Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):317-24. — View Citation

Wilcock G, Möbius HJ, Stöffler A; MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002 Nov;17(6):297-305. — View Citation

Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999 Feb;14(2):135-46. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Neuropsychiatric Inventory (NPI)	NPI:12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, nighttime behavior. A screening question is asked about each sub-domain. If the responses to these questions indicate that the patient has problems with a particular sub-domain of behavior, the caregiver is only then asked all the questions about that domain, rating the frequency of the symptoms on a 4-point scale, their severity on a 3-point scale, and the distress the symptom causes them on a 5-point scale. Severity(1=Mild to 3=Severe),frequency(1=occasionally to 4=very frequently) scales recorded for each domain; frequency*severity=each domain score(range 0-12). Total score=sum of each domain score(range 0-144);higher score=greater behavioral disturbances;negative change score from baseline=improvement.	Baseline, 26 weeks
Primary	Clinical Global Impression of Change (CGIC)	The scale is rated on a 7-point scale, using a range of responses from 1 (very much improved) through 7 (very much worse). The clinician compares the participant's current condition to the condition at admission to the project.	26 Weeks
Secondary	Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test	Clinical dementia rating sum of boxes CDR-SB (0-18) high scores indicate high impairment.; Functional activities questionnaire FAQ (0-30) high scores indicate high impairment.; Texas functional living scale TFLS (0 to 52) high scores suggest better instrumental activities of daily living functioning.; Mini-Mental State Examination MMSE (0-30) low scores indicate low cognition. The executive interview EXIT25 (0 to 50) high scores indicate more executive impairment.; A modified unified Parkinson's disease rating scale UPDRS (0-199) high scores indicate worse disability.; Boston naming test (0-15) low scores indicate more retrieval difficulties.	Baseline and 26 Weeks
Secondary	Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards	Letter fluency, score is number of words recalled starting with a specified letter for 60 seconds. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials for the score. Low scores indicate high impairment; Category fluency, score is number of items generated belonging to a specific category (such as animals) in 60 seconds, low scores indicate high impairment.; Digit symbol, score is number of symbols that correctly corresponded to the random numerals entered in the form in 90 seconds. Participants are given a table of numerals with matching symbols, and a form with random numerals with open spaces. Low scores indicate high impairment.; Digits backwards, score is number of digits backwards recalled (range: 0-14), The participant hears a list of digits and is asked to repeat the digits backwards. Low scores indicate high impairment.	Baseline and 26 Weeks
Secondary	Number of Participants Starting Antipsychotic Therapy		26 weeks

External Links

•   UCSF Memory and Aging Center