A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease

NCT02017340 | Completed Phase 3 DMC

• 3 other identifiers: NILVAD20122012-002764-27279093
• Study Type: interventional
• Target: 511
• Locations: 9 countries
• Sites: 23

Brief Summary

Alzheimer's disease (AD) is an ever-increasing public health concern among the aging population and is the most common form of dementia affecting more than 15 million individuals worldwide and around 5 million Europeans. The direct and indirect costs of AD and other dementias amount to more than €440,000 million each year (www.alz.org, 2010). Even modest therapeutic advances that delay disease onset and progression could significantly reduce the global burden of the disease and the level of care required by patients. While there are symptomatic-based drug therapies available for AD, these medications do not prevent the disease process itself. There is therefore an imperative to develop new treatments for AD that have disease modifying effects. This double-blind placebo controlled study will test the efficacy and safety of nilvadipine in 500 subjects with mild to moderate AD over a treatment period of 18 months. There is a strong scientific rationale for this study: Nilvadipine, a licensed calcium channel enhances Aß clearance from brain and restores cortical perfusion in mouse models of AD. Nilvadipine is safe and well tolerated in AD patients and clinical studies with this medication have shown stabilization of cognitive decline and reduced incidence of AD, pointing to both symptomatic and disease modifying benefits. Male and female patients with mild to moderate AD aged between 50 and 90 with a range of medical morbidities and frailty will be included in the study. If this trial is successful, nilvadipine would represent an advance in the treatment of AD patients and would have a major impact on the health and social care costs incurred in Europe by this neurodegenerative disorder. Furthermore, the creation of the NILVAD network will support future clinical trials and research innovation in AD across Europe.

Conditions

Alzheimer's Disease

Keywords

Alzheimer's Disease; Investigator-driven clinical trial; Nilvadipine; Calcium Channel blocker; Elderly; Therapeutic Intervention

Outcome Measures

Primary Outcomes (1)

• Alzheimer's Disease Assessment Scale (ADAS) Cog

  The Alzheimer's Disease Assessment Scale (Cognitive) (Mohs et al. 1983) ADAS-cog 12 is a primary efficacy outcome measure, and includes 12 items of cognitive evaluation, namely immediate word recall, naming objects and fingers, commands, constructional praxis, ideational praxis, orientation, word recognition, remembering test instructions, spoken language ability, word-finding difficulty in spontaneous speech, comprehension \& delayed recall. A higher ADAS-cog score indicates a poorer cognitive function.

  18 months

Secondary Outcomes (2)

• Clinical Dementia Rating Scale Sum of Boxes (CDR-sb)

  18 months

• Disability Assessment for Dementia (DAD)

  18 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

250 patients will receive the placebo

Drug: Placebo

Nilvadipine

ACTIVE COMPARATOR

250 patient will receive the active drug Nilvadipine 8mg

Drug: Nilvadipine

Interventions

Nilvadipine DRUG

8mg of Nilvadipine taken once a day at lunch time for 78 weeks

Also known as: Also known as Nilvadil (Brand Name)

Nilvadipine

Placebo DRUG

8mg Placebo tablet taken once a day at lunch time for 78 weeks

Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age range: Adult subjects, males and females over age 50 years.
• Prior diagnosis of mild to moderate probable AD based on NINCDS-ADRDA criteria (see Appendix B) and
• Standardised Mini-Mental State Examination (SMMSE) score \> 12 on stable dose (\>3 months of cholinesterase inhibitor and or memantine). Subjects who are not on cholinesterase inhibitors or memantine due to poor tolerability and/or who will not require treatment with these medications during the course of the study can be included.
• Collateral informants such as a spouse, family member, close friend. The informant must have close contact with the subject and agree to monitor/manage study drug adherence, observe for possible adverse events, assist with psychometric measures requiring informant information, and accompany the subject to all evaluation visits.
• Fluency in relevant language sufficient to reliably complete all study assessments.
• Systolic BP \> 100 mmHg but ≤ 159 mmHg, and diastolic BP \> 65 mmHg but ≤ 99 mmHg on resting office based BP measurements, or a Systolic BP \> 105 mmHg but ≤ 140 mmHg, and diastolic BP \> 70 mmHg but ≤ 90 mmHg on ABPM measurement

You may not qualify if:

• Subjects with co-morbid dementia due to other neurological disorders such as Parkinson's disease, vascular dementia, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, or multiple sclerosis, as well as subjects with HIV disease, neurosyphilis, history of significant head trauma with loss of consciousness followed by persistent neurological deficits, known structural brain abnormalities, or any other condition known to interfere with cognitive function.
• Subjects currently taking any calcium channel blocker or Beta-blocker
• Subjects who in the opinion of the investigator, have a medical condition that would preclude them from participating in the study (e.g.hemodynamically significant coronary artery disease., chronic heart failure, syncope within the past year, significant valvular heart disease i.e. severe aortic and mitral stenosis.. symptomatic orthostatic hypotension within the last year, subjects requiring more than one agent to control BP.), or subjects who in the opinion of the investigator are unlikely to complete per protocol due to care issues etc:
• Current Axis I diagnosis of schizophrenia, bipolar disorder, major depression. Subjects who are currently or who have within the past year met criteria for drug or alcohol abuse or dependence.
• Pregnant women or women who may possibly become pregnant.
• Subjects with a history of hypersensitivity to nilvadipine (Nivadil).
• Subjects who have taken an investigational or other unapproved drug during the 30 days or five half-lives, whichever is longer, prior to baseline.
• Subjects who are participating in other research studies.
• Patients with a SBP of ≤ 100 mmHg and/or a DBP of ≤ 65 mmHg on office based BP measurements, or a SBP ≤ 105 mmHg and/or a DBP of ≤ 70 mmHg on ABPM will not be included in the study.

Sponsors & Collaborators

• Prof Brian Lawlor: lead
• University of Dublin, Trinity College: collaborator
• Molecular Medicine Ireland LBG: collaborator
• Alzheimer Europe: collaborator
• Archer Pharmaceuticals, Inc.: collaborator
• E-Search Limited: collaborator
• University College Dublin: collaborator
• King's College London: collaborator
• Istituto Di Ricerche Farmacologiche Mario Negri: collaborator
• University Hospital, Lille: collaborator
• University of Ulm: collaborator
• Szeged University: collaborator
• Göteborg University: collaborator
• University College Cork: collaborator
• Aristotle University Of Thessaloniki: collaborator
• Stichting Katholieke Universiteit: collaborator

Study Sites (23)

Centre Hospitalier Universitaire d'Amiens (CHU Amiens)

Amiens, France

Location

Centre Hospitalier Universitaire de Bethune (CH Bethune)

Béthune, France

Location

Centre Hospitalier Universitaire de Caen (CHU Caen)

Caen, France

Location

Centre Hospitalier Universitaire de Calais (CHU Calais)

Calais, France

Location

Centre Hospitalier Universitaire de Lens (CHU Lens)

Lens, France

Location

Centre Hospitalier Regional et Universitaire de Lille (CHRU Lille)

Lille, France

Location

Centre Hospitalier Universitaire de Saint Philibert (GHICL)

Lille, France

Location

University of Ulm

Ulm, Germany

Location

"G. Papanicolaou" Hospital

Athens, Greece

Location

"G.Papageorgiou" Hospital

Athens, Greece

Location

AXEPA Hospital

Athens, Greece

Location

Szeged University

Szeged, Hungary

Location

University College Cork

Cork, Ireland

Location

St James Hospital

Dublin, Ireland

Location

Hospital of Brescia

Brescia, Italy

Location

Hospital Castellanza

Castellanza, Italy

Location

Hospital of Genoa

Genoa, Italy

Location

Hospital of Milan

Milan, Italy

Location

Hospital of Arnhem

Arnhem, Netherlands

Location

Hospital of Maastricht

Maastricht, Netherlands

Location

Hospital of Nijmegen

Nijmegen, Netherlands

Location

Gothenburg Univeristy

Gothenburg, Sweden

Location

Kings College London

London, United Kingdom

Location

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• Dyer AH, Lawlor B, Kennelly SP; NILVAD Study Group. Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: data from NILVAD. BMC Geriatr. 2020 Mar 30;20(1):117. doi: 10.1186/s12877-020-01531-w.

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• Abdullah L, Crawford F, Tsolaki M, Borjesson-Hanson A, Olde Rikkert M, Pasquier F, Wallin A, Kennelly S, Ait-Ghezala G, Paris D, Hendrix S, Blennow K, Lawlor B, Mullan M. The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial. Front Neurol. 2020 Mar 6;11:149. doi: 10.3389/fneur.2020.00149. eCollection 2020.

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• de Heus RAA, Olde Rikkert MGM, Tully PJ, Lawlor BA, Claassen JAHR; NILVAD Study Group. Blood Pressure Variability and Progression of Clinical Alzheimer Disease. Hypertension. 2019 Nov;74(5):1172-1180. doi: 10.1161/HYPERTENSIONAHA.119.13664. Epub 2019 Sep 23.

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• de Jong DLK, de Heus RAA, Rijpma A, Donders R, Olde Rikkert MGM, Gunther M, Lawlor BA, van Osch MJP, Claassen JAHR. Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2019 Aug;74(2):413-420. doi: 10.1161/HYPERTENSIONAHA.119.12892. Epub 2019 Jun 17.

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• de Heus RAA, Donders R, Santoso AMM, Olde Rikkert MGM, Lawlor BA, Claassen JAHR; Nilvad Study Group. Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension. J Am Heart Assoc. 2019 May 21;8(10):e011938. doi: 10.1161/JAHA.119.011938.

  PMID: 31088188 DERIVED

• Lawlor B, Segurado R, Kennelly S, Olde Rikkert MGM, Howard R, Pasquier F, Borjesson-Hanson A, Tsolaki M, Lucca U, Molloy DW, Coen R, Riepe MW, Kalman J, Kenny RA, Cregg F, O'Dwyer S, Walsh C, Adams J, Banzi R, Breuilh L, Daly L, Hendrix S, Aisen P, Gaynor S, Sheikhi A, Taekema DG, Verhey FR, Nemni R, Nobili F, Franceschi M, Frisoni G, Zanetti O, Konsta A, Anastasios O, Nenopoulou S, Tsolaki-Tagaraki F, Pakaski M, Dereeper O, de la Sayette V, Senechal O, Lavenu I, Devendeville A, Calais G, Crawford F, Mullan M; NILVAD Study Group. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med. 2018 Sep 24;15(9):e1002660. doi: 10.1371/journal.pmed.1002660. eCollection 2018 Sep.

  PMID: 30248105 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

nilvadipine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Brian Lawlor, Prof

  University of Dublin, Trinity College

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Project Coordinator

Study Record Dates

• First Submitted: December 16, 2013
• First Posted: December 20, 2013
• Study Start: April 24, 2013
• Primary Completion: December 16, 2016
• Study Completion: December 16, 2016
• Last Updated: March 6, 2017

Record last verified: 2017-03

Locations

SE (1); FR (7); IE (2); NL (3); DE (1); GR (3); GB (1); HU (1); IT (4)