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Association of nimodipine and choline alphoscerate in the treatment of cognitive impairment in patients with cerebral small vessel disease: study protocol for a randomized placebo-controlled trial—the CONIVaD trial

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Abstract

Background

Vascular cognitive impairment (VCI) is an extremely disabling condition that includes post-stroke dementia and VCI caused by cerebral small vessel disease (SVD). Currently, there is no approved treatment for this condition. Drugs active on the cholinergic pathway have been tested in VCI patients showing positive but limited efficacy. The calcium-antagonist nimodipine also showed some moderate positive effects in VCI patients.

Aims

CONIVaD (choline alphoscerate and nimodipine in vascular dementia) is a pilot, single-center, double-blinded, randomized trial aimed to assess whether the association of choline alphoscerate and nimodipine is more effective than nimodipine alone in reducing cognitive decline in patients with SVD and mild-to-moderate cognitive impairment.

Methods

All patients are evaluated at baseline and after 12 months with: (1) clinical, daily functions, quality of life, and mood assessment and (2) extensive neuropsychological evaluation. After the baseline evaluation, patients are randomly assigned to one of the two arms of treatment: (1) nimodipine 90 mg/die t.i.d plus placebo b.i.d and (2) nimodipine 90 mg t.i.d plus choline alphoscerate 1200 mg/die b.i.d. for a total of 12 months. The primary endpoint is cognitive decline, expressed as the loss of at least two points on the Montreal Cognitive Assessment at 12 months. Secondary endpoints include safety and tolerability, functional, quality of life, and neuropsychological measures.

Discussion

CONIVaD study is the first randomized controlled trial to examine the cognitive efficacy of combined choline alphoscerate–nimodipine treatment in VCI patients. Results of this pilot study will serve as a methodological basis for other clinical controlled, multicentric, double-blinded, and randomized trials.

Trial registration

Clinical Trial NCT03228498. Registered 25 July 2017.

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References

  1. O’Brien JT, Erkinjuntti T, Reisberg B et al (2003) Vascular cognitive impairment. Lancet Neurol 2:89–98

    PubMed  Google Scholar 

  2. Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701

    PubMed  Google Scholar 

  3. Wardlaw JM, Smith EE, Biessels GJ et al (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838

    PubMed  PubMed Central  Google Scholar 

  4. Pantoni L (2004) Treatment of vascular dementia: evidence from trials with non-cholinergic drugs. J Neurol Sci 226:67–70

    CAS  PubMed  Google Scholar 

  5. Smith EE, Cieslak A, Barber P et al (2017) Therapeutic strategies and drug development for vascular cognitive impairment. J Am Heart Assoc 1:1. https://doi.org/10.1161/JAHA.117.005568

    Article  Google Scholar 

  6. Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam MM (1998) Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 121:2249–2257

    PubMed  Google Scholar 

  7. Wilkinson D, Doody R, Helme R et al (2003) Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 61:479–486

    CAS  PubMed  Google Scholar 

  8. Black S, Román GC, Geldmacher DS et al (2003) Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 34:2323–2330

    CAS  PubMed  Google Scholar 

  9. Dichgans M, Markus HS, Salloway S et al (2008) Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol 7:310–318

    CAS  PubMed  Google Scholar 

  10. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV (2002) Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomized trial. Lancet 359:1283–1290

    PubMed  Google Scholar 

  11. Auchus AP, Brashear HR, Salloway S, Korczyn AD, De Deyn PP, Gassmann-Mayer C (2007) Galantamine treatment of vascular dementia: a randomized trial. Neurology 69:448–458

    CAS  PubMed  Google Scholar 

  12. Ballard C, Sauter M, Scheltens P et al (2008) Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Curr Med Res Opin 24:2561–2574

    CAS  PubMed  Google Scholar 

  13. Narasimhalu K, Effendy S, Sim CH et al (2010) A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease. Acta Neurol Scand 121:217–224

    CAS  PubMed  Google Scholar 

  14. Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F (2002) Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 33:1834–1839

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Kavirajan H, Schneider LS (2007) Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 6:782–792

    CAS  PubMed  Google Scholar 

  17. Gorelick PB, Scuteri A, Black SE et al (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713

    PubMed  PubMed Central  Google Scholar 

  18. Wecker L, Schmidt DE (1979) Central cholinergic function in the rat relationship to choline administration. Life Sci 25:375–384

    CAS  PubMed  Google Scholar 

  19. Secades JJ (2016) Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 63:1–73

    Google Scholar 

  20. Alvarez-Sabín J, Ortega G, Jacas C et al (2013) Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis 35:146–154

    PubMed  Google Scholar 

  21. Fioravanti M, Yanagi M (2005) Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev 2:CD000269

    Google Scholar 

  22. Di Perri R, Coppola G, Ambrosio LA, Grasso A, Puca FM, Rizzo M (1991) A multicentre trial to evaluate the efficacy and tolerability of α-glycerylphosphoryl-choline versus cytidine diphosphocholine in patients with vascular dementia. J Int Med Res 19:330–341

    PubMed  Google Scholar 

  23. Muratorio A, Bonuccelli U, Nuti A, Battistini N, Passero S (1992) A neurotropic approach to the treatment of multi-infarct dementia using L-α-glyceryl-phoshorylcholine. Curr Ther Res 52:741–751

    Google Scholar 

  24. Pantoni L, Carosi M, Amigoni S, Mascalchi M, Inzitari D (1996) A preliminary open trial with nimodipine in patients with cognitive impairment and leukoaraiosis. Clin Neuropharmacol 19:497–506

    CAS  PubMed  Google Scholar 

  25. Pantoni L, Bianchi C, Beneke M, Inzitari D, Wallin A, Erkinjuntti T (2000) The scandinavian multi-infarct dementia trial: a double blind, placebo-controlled trial on nimodipine in multi-infarct dementia. J Neurol Sci 175:116–123

    CAS  PubMed  Google Scholar 

  26. Pantoni L, Rossi R, Inzitari D et al (2000) Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the scandinavian multi-infarct dementia trial. J Neurol Sci 175:124–134

    CAS  PubMed  Google Scholar 

  27. Pantoni L, del Ser T, Soglian AG et al (2005) Efficacy and safety of nimodipine in subcortical vascular dementia: a randomized placebo-controlled trial. Stroke 36:619–624

    CAS  PubMed  Google Scholar 

  28. Farkas E, De Jong GI, Apró E, Keuker JI, Luiten PG (2001) Calcium antagonists decrease capillary wall damage in aging hypertensive rat brain. Neurobiol Aging 22:299–309

    CAS  PubMed  Google Scholar 

  29. de Jong GI, Traber J, Luiten PG (1992) Formation of cerebrovascular anomalies in the ageing rat is delayed by chronic nimodipine application. Mech Ageing Dev 64:255–272

    PubMed  Google Scholar 

  30. Hu M, Liu Z, Lv P et al (2017) Nimodipine activates neuroprotective signaling events and inactivates autophages in the VCID rat hippocampus. Neurol Res 39:904–909

    CAS  PubMed  Google Scholar 

  31. López-Arrieta JM, Birks J (2002) Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 3:CD000147

    Google Scholar 

  32. Erkinjuntti T, Inzitari D, Pantoni L et al (2000) Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials. Is a focus on subcortical vascular dementia a solution? Ann N Y Acad Sci 903:262–272

    CAS  PubMed  Google Scholar 

  33. Poggesi A, Salvadori E, Valenti R et al (2014) The Florence VAS-COG clinic: a model for the care of patients with cognitive and behavioral disturbances consequent to cerebrovascular diseases. J Alzheimers Dis 42:453–461

    Google Scholar 

  34. Morris JC (1993) The clinical dementia rating (CDR): current version and scoring rules. Neurology 43:2412–2414

    CAS  PubMed  Google Scholar 

  35. Pantoni L, Basile AM, Pracucci G et al (2005) Impact of age-related cerebral white matter changes on the transition to disability—the LADIS study: rationale, design and methodology. Neuroepidemiology 24:51–62

    PubMed  Google Scholar 

  36. Van Swieten JC, Hijdra A, Koudstaal PJ, Van Gijn J (1990) Grading white matter lesions on CT and MRI: a simple scale. J Neurol Neurosurg Psychiatry 53:1080–1083

    PubMed  PubMed Central  Google Scholar 

  37. Winblad B, Palmer K, Kivipelto M et al (2004) Mild cognitive impairment—beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment. J Intern Med 256:240–246

    CAS  PubMed  Google Scholar 

  38. McKhann GM, Knopman DS, Chertkow H et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269

    PubMed  PubMed Central  Google Scholar 

  39. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, Arlington

    Google Scholar 

  40. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW (1963) Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA 185:914–919

    CAS  PubMed  Google Scholar 

  41. Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9:179–186

    CAS  PubMed  Google Scholar 

  42. Gelinas I, Gauthier L, McIntire M, Gauthier S (1999) Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther 53:471–483

    CAS  PubMed  Google Scholar 

  43. van Straten A, de Haan RJ, Limburg M, Schuling J, Bossuyt PM, van den Bos GA (1997) A stroke-adapted 30-item version of the sickness impact profile to assess quality of life (SA-SIP30). Stroke 28:2155–2161

    PubMed  Google Scholar 

  44. Radloff LS (1977) The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1:385–401

    Google Scholar 

  45. Kaufer D, Cummings J, Ketchel P et al (2000) Validation of the NPI-Q, a Brief clinical Form of the Neuropsychiatric Inventory. J Neuropsychiatry Cli Neurosci 12:233–239

    CAS  Google Scholar 

  46. Salvadori E, Poggesi A, Pracucci G, Inzitari D, Pantoni L, VMCI-Tuscany Study Group (2015) Development and psychometric properties of a neuropsychological battery for mild cognitive impairment with small vessel disease: the VMCI-Tuscany Study. J Alzheimers Dis 43:1313–1323

    PubMed  Google Scholar 

  47. SAS Institute Inc (2015) Base SAS 9.4 procedures guide, 5th edn. SAS Institute Inc, Cary. http://support.sas.com

  48. Poggesi A, Salvadori E, Pantoni L et al (2012) Risk and determinants of dementia in patients with mild cognitive impairment and brain subcortical vascular changes: a study of clinical, neuroimaging, and biological markers. The VMCI-tuscany study: rationale, design, and methodology. Int J Alzheimers Dis. https://doi.org/10.1155/2012/608013

    Article  PubMed  PubMed Central  Google Scholar 

  49. Borm GF, Fransen J, Lemmens WA (2007) A simple sample size formula for analysis of covariance in randomized clinical trials. J Clin Epidemiol 60:1234–1238

    PubMed  Google Scholar 

  50. Salvadori E, Poggesi A, Valenti R et al (2016) Operationalizing mild cognitive impairment criteria in small vessel disease: the VMCI-Tuscany Study. Alzheimers Dement 12:407–418

    PubMed  Google Scholar 

  51. Salvadori E, Poggesi A, Pracucci G et al (2018) Application of the DSM-5 criteria for major neurocognitive disorder to vascular MCI patients. Dement Geriatr Cogn Dis Extra 8:104–116

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank the staff of the Neurology and Geriatric units at the Careggi University Hospital of Florence and the General Medicine physicians for help in referring patients.

Funding

MDM Spa Company (Monza, Italy) provided the active drugs and placebo as free donation. The company had no role in trial design, conduction and will have no role in data analyses.

Author information

Author notes

  1. Emilia Salvadori and Anna Poggesi contributed equally to this work.

Authors and Affiliations

  1. NEUROFARBA Department, University of Florence, Florence, Italy

    Emilia Salvadori, Anna Poggesi, Ida Donnini, Valentina Rinnoci, Guido Chiti, Martina Squitieri, Laura Tudisco & Anna Melone

  2. Psychiatry Unit, Department of Health Sciences, University of Florence, Florence, Italy

    Fabio Fierini

  3. Stroke Unit, Emergency Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy

    Francesca Pescini

  4. Department of Biomedical and Clinical Sciences, ‘L. Sacco’ Hospital, University of Milan, Via Giovanni Battista Grassi 74, 20157, Milan, Italy

    Leonardo Pantoni

Authors
  1. Emilia Salvadori
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Corresponding author

Correspondence to Leonardo Pantoni.

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Conflict of interest

AP, FP, ES, ID, RV, GC, MS, LT, AM, and FF report no disclosures. LP: member of the editorial boards of Cerebrovascular Diseases, Acta Neurologica Scandinavica, Neurological Sciences and European Stroke Journal; and section editor (Vascular Cognitive Impairment) of Stroke.

Ethics approval and consent to participate

The study is carried in accordance with the 1964 Helsinki Declaration and its later amendments and with the ethical standards of the institutional ethics committee, and was approved by the ethics committee of the Careggi University Hospital, Florence, Italy.

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Informed consent was obtained from all individual participants included in the study.

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Salvadori, E., Poggesi, A., Donnini, I. et al. Association of nimodipine and choline alphoscerate in the treatment of cognitive impairment in patients with cerebral small vessel disease: study protocol for a randomized placebo-controlled trial—the CONIVaD trial. Aging Clin Exp Res 32, 449–457 (2020). https://doi.org/10.1007/s40520-019-01229-z

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