PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

NCT03507374 | Terminated Early Phase 1 DMC FDA Drug

• 1 other identifier: 00104839
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a randomized double blind placebo-controlled pilot study using a repeated measures design in which participants with acute ischemic stroke and intracranial atherosclerotic disease are randomized to either drug or placebo.

Conditions

Stroke; Intracranial Atherosclerosis; Intraplaque Hemorrhage

Keywords

Stroke; alirocumab; Intracranial Atherosclerosis; Intraplaque Hemorrhage; atorvastatin; praluent

Outcome Measures

Primary Outcomes (1)

• Vessel Wall MRI

  Our primary outcome measures will be to assess the Vessel Wall MRI on Day 365 and compare it to day 1.The primary endpoint is nominal change in the composite percent atheroma volume (PAV) of the stroke parent artery and additional intra- or extracranial cerebrovasculature arteries with atherosclerosis (≥ 25% stenosis) from baseline to week 52. We will use measure PAV on vessel wall MRI (vwMRI), which evaluates all arteries from the aortic arch to the distal intracranial vasculature in a single scan. The primary endpoint will be analyzed for both: 1) the composite PAV of the stroke parent artery and any additional intra- or extracranial arteries that have at least 25% stenosis, and 2) separately for the PAV of the stroke parent artery. The PAV measurements will be performed using the validated MRI-PlaqueView software. Stenosis of the stroke parent artery and all additional arteries included in the composite PAV will be measured using standard methodology and also be evaluated as

  Day 1 and Day 365

Secondary Outcomes (1)

• Post-Contrast Plaque Enhancement

  Day 1

Other Outcomes (3)

• Mechanism of Alirocumab's effect

  Day 1 and Day 365

• Lab Assessment

  Baseline visit and Day 365

• Clinical Outcomes

  Baseline and Day 365

Study Arms (2)

Placebo Comparator

PLACEBO COMPARATOR

After review of eligibility criteria, 20 patients will be randomized to the placebo arm of the study where patient will administer one subcutaneous injection of placebo every two weeks for a total of 52 weeks. Additionally, per standard-of-care, patient will also be treated with atorvastatin 40-80 mg.

Drug: Placebo

Active Comparator

ACTIVE COMPARATOR

After review of eligibility criteria, 20 patients will be randomized to receive the investigational treatment of alirocumab 150mg which will be administered subcutaneously with a single-dose pre-filled pen syringe every 2 weeks for a total of 52 weeks. Additionally, per standard-of-care, patient will also be treated with atorvastatin 40-80 mg

Drug: Alirocumab

Interventions

Alirocumab DRUG

Alirocumab is approved by the FDA as a secondary treatment for high cholesterol for adults whose cholesterol can not be controlled by diet and/or statin treatment. Additionally, Alirocumab works to inhibit the PCSK9 protein.

Also known as: Praluent

Active Comparator

Placebo DRUG

Placebo to be administered subcutaneously every 2 weeks identical to active drug (alirocumab)

Placebo Comparator

Eligibility Criteria

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

You may qualify if:

• Adult patients, ≥ 18 years of age
• Ischemic stroke (≤ 1 month from onset) in one major vascular territory on diffusion-weighted MRI
• ICAD plaque of a "major intracranial artery," causing \>25% and \<99% stenosis
• Eligible arteries: vertebral (V4), basilar, PCA (P1, P2), MCA (M1, M2), terminal ICA, and ACA (A1)
• Able to tolerate high-dose statin (atorvastatin 40-80 mg)

You may not qualify if:

• Stroke mechanism other than ICAD, including history of atrial fibrillation, hypercoagulability, ipsilateral arterial dissection or carotid stenosis \>50%, and rare causes of stroke such as vasculitis or CADASIL
• Bihemispheric stroke or simultaneous stroke in the anterior and posterior circulation
• Positive pregnancy test
• Gadolinium or PCSK9 inhibitor allergy
• Acute or chronic kidney disease with eGFR\<30 ml/min/1.73m2
• Pacemaker or other MRI contraindications per American College of Radiology guidelines33
• Inability to return for 1-year follow-up clinic visit and vwMRI

Sponsors & Collaborators

• University of Utah: lead
• Regeneron Pharmaceuticals: collaborator

Study Sites (1)

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (39)

• Suri MF, Johnston SC. Epidemiology of intracranial stenosis. J Neuroimaging. 2009 Oct;19 Suppl 1:11S-6S. doi: 10.1111/j.1552-6569.2009.00415.x.

  PMID: 19807851 BACKGROUND

• Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013 Nov;12(11):1106-14. doi: 10.1016/S1474-4422(13)70195-9.

  PMID: 24135208 BACKGROUND

• Arenillas JF. Intracranial atherosclerosis: current concepts. Stroke. 2011 Jan;42(1 Suppl):S20-3. doi: 10.1161/STROKEAHA.110.597278. Epub 2010 Dec 16.

  PMID: 21164126 BACKGROUND

• Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke. 2014 Jan;16(1):27-35. doi: 10.5853/jos.2014.16.1.27. Epub 2014 Jan 31.

  PMID: 24741562 BACKGROUND

• Koo J. The Latest Information on Intracranial Atherosclerosis: Diagnosis and Treatment. Interv Neurol. 2015 Oct;4(1-2):48-50. doi: 10.1159/000438779. Epub 2015 Sep 18.

  PMID: 26600797 BACKGROUND

• Wang YL, Pan YS, Zhao XQ, Wang D, Johnston SC, Liu LP, Meng X, Wang AX, Wang CX, Wang YJ; CHANCE investigators. Recurrent stroke was associated with poor quality of life in patients with transient ischemic attack or minor stroke: finding from the CHANCE trial. CNS Neurosci Ther. 2014 Dec;20(12):1029-35. doi: 10.1111/cns.12329. Epub 2014 Oct 13.

  PMID: 25307297 BACKGROUND

• Wang A, Wu L, Wang X, Zhao X, Wang C, Liu L, Zheng H, Cao Y, Wang Y, Wang Y; China National Stroke Registry investigators. Effect of recurrent stroke on poor functional outcome in transient ischemic attack or minor stroke. Int J Stroke. 2016 Oct;11(7):NP80. doi: 10.1177/1747493016641954. Epub 2016 Mar 24. No abstract available.

  PMID: 27012273 BACKGROUND

• Hong KS, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for current trial design. Circulation. 2011 May 17;123(19):2111-9. doi: 10.1161/CIRCULATIONAHA.109.934786. Epub 2011 May 2.

  PMID: 21536995 BACKGROUND

• Chaturvedi S, Sacco RL. How recent data have impacted the treatment of internal carotid artery stenosis. J Am Coll Cardiol. 2015 Mar 24;65(11):1134-43. doi: 10.1016/j.jacc.2014.12.045.

  PMID: 25790886 BACKGROUND

• Bonati LH, Dobson J, Featherstone RL, Ederle J, van der Worp HB, de Borst GJ, Mali WP, Beard JD, Cleveland T, Engelter ST, Lyrer PA, Ford GA, Dorman PJ, Brown MM; International Carotid Stenting Study investigators. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet. 2015 Feb 7;385(9967):529-38. doi: 10.1016/S0140-6736(14)61184-3. Epub 2014 Oct 14.

  PMID: 25453443 BACKGROUND

• Brott TG, Howard G, Roubin GS, Meschia JF, Mackey A, Brooks W, Moore WS, Hill MD, Mantese VA, Clark WM, Timaran CH, Heck D, Leimgruber PP, Sheffet AJ, Howard VJ, Chaturvedi S, Lal BK, Voeks JH, Hobson RW 2nd; CREST Investigators. Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery Stenosis. N Engl J Med. 2016 Mar 17;374(11):1021-31. doi: 10.1056/NEJMoa1505215. Epub 2016 Feb 18.

  PMID: 26890472 BACKGROUND

• Paraskevas KI, Mikhailidis DP, Veith FJ, Spence JD. Definition of Best Medical Treatment in Asymptomatic and Symptomatic Carotid Artery Stenosis. Angiology. 2016 May;67(5):411-9. doi: 10.1177/0003319715624526. Epub 2015 Dec 31.

  PMID: 26721504 BACKGROUND

• Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, Sila CA, Jovin TG, Romano JG; Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005 Mar 31;352(13):1305-16. doi: 10.1056/NEJMoa043033.

  PMID: 15800226 BACKGROUND

• den Hartog AG, Achterberg S, Moll FL, Kappelle LJ, Visseren FL, van der Graaf Y, Algra A, de Borst GJ; SMART Study Group. Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease. Stroke. 2013 Apr;44(4):1002-7. doi: 10.1161/STROKEAHA.111.669267. Epub 2013 Feb 12.

  PMID: 23404720 BACKGROUND

• Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, Cates CU, Creager MA, Fowler SB, Friday G, Hertzberg VS, McIff EB, Moore WS, Panagos PD, Riles TS, Rosenwasser RH, Taylor AJ. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery DiseaseA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery Developed in Collaboration With the American Academy of Neurology and Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2011 Feb 22;57(8):e16-e94.

  BACKGROUND

• Windecker S, Stortecky S, Stefanini GG, da Costa BR, Rutjes AW, Di Nisio M, Silletta MG, Maione A, Alfonso F, Clemmensen PM, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head S, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter D, Schauerte P, Sousa Uva M, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A, Kolh P, Juni P. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ. 2014 Jun 23;348:g3859. doi: 10.1136/bmj.g3859.

  PMID: 24958153 BACKGROUND

• Pursnani S, Korley F, Gopaul R, Kanade P, Chandra N, Shaw RE, Bangalore S. Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials. Circ Cardiovasc Interv. 2012 Aug 1;5(4):476-90. doi: 10.1161/CIRCINTERVENTIONS.112.970954. Epub 2012 Aug 7.

  PMID: 22872053 BACKGROUND

• de Havenon A, Yuan C, Tirschwell D, Hatsukami T, Anzai Y, Becker K, Sultan-Qurraie A, Mossa-Basha M. Nonstenotic Culprit Plaque: The Utility of High-Resolution Vessel Wall MRI of Intracranial Vessels after Ischemic Stroke. Case Rep Radiol. 2015;2015:356582. doi: 10.1155/2015/356582. Epub 2015 Aug 6.

  PMID: 26346855 BACKGROUND

• Kim JM, Jung KH, Sohn CH, Moon J, Shin JH, Park J, Lee SH, Han MH, Roh JK. Intracranial plaque enhancement from high resolution vessel wall magnetic resonance imaging predicts stroke recurrence. Int J Stroke. 2016 Feb;11(2):171-9. doi: 10.1177/1747493015609775.

  PMID: 26783308 BACKGROUND

• Gutierrez J, Elkind MS, Virmani R, Goldman J, Honig L, Morgello S, Marshall RS. A pathological perspective on the natural history of cerebral atherosclerosis. Int J Stroke. 2015 Oct;10(7):1074-80. doi: 10.1111/ijs.12496. Epub 2015 Apr 8.

  PMID: 25854637 BACKGROUND

• Mossa-Basha M, Hwang WD, De Havenon A, Hippe D, Balu N, Becker KJ, Tirschwell DT, Hatsukami T, Anzai Y, Yuan C. Multicontrast high-resolution vessel wall magnetic resonance imaging and its value in differentiating intracranial vasculopathic processes. Stroke. 2015 Jun;46(6):1567-73. doi: 10.1161/STROKEAHA.115.009037. Epub 2015 May 7.

  PMID: 25953365 BACKGROUND

• Teng Z, Peng W, Zhan Q, Zhang X, Liu Q, Chen S, Tian X, Chen L, Brown AJ, Graves MJ, Gillard JH, Lu J. An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery. Eur Radiol. 2016 Jul;26(7):2206-14. doi: 10.1007/s00330-015-4008-5. Epub 2015 Sep 16.

  PMID: 26376883 BACKGROUND

• Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384. doi: 10.1001/jama.2016.16951.

  PMID: 27846344 BACKGROUND

• Gupta A, Baradaran H, Al-Dasuqi K, Knight-Greenfield A, Giambrone AE, Delgado D, Wright D, Teng Z, Min JK, Navi BB, Iadecola C, Kamel H. Gadolinium Enhancement in Intracranial Atherosclerotic Plaque and Ischemic Stroke: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2016 Aug 15;5(8):e003816. doi: 10.1161/JAHA.116.003816.

  PMID: 27528408 BACKGROUND

• Hamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic spectrum of pituitary infundibulum lesions. AJR Am J Roentgenol. 2007 Mar;188(3):W223-32. doi: 10.2214/AJR.05.2027.

  PMID: 17312027 BACKGROUND

• de Havenon A, Chauhan N, Majersik J, Parker D, McNally. Determinants of Intracranial Atherosclerotic Enhancement on Vessel Wall MRI in Patients with Acute Ischemic Stroke. Houston, TX; 2017 [cited 2017 Feb 13]. Available from: http://www.abstractsonline.com/pp8/#!/4172/presentation/9649

  BACKGROUND

• de Havenon A, Chauhan N, Kim S, Hadley J, Parker D, Majersik J, McNally S. Determinants of Symptomatic Intracranial Atherosclerotic Plaque Enhancement on 3D DANTE T1-SPACE Vessel Wall MRI and Relationship to Recurrent Stroke or TIA. Honolulu, HI; 2017.

  BACKGROUND

• Hosseini AA, Kandiyil N, Macsweeney ST, Altaf N, Auer DP. Carotid plaque hemorrhage on magnetic resonance imaging strongly predicts recurrent ischemia and stroke. Ann Neurol. 2013 Jun;73(6):774-84. doi: 10.1002/ana.23876. Epub 2013 Jun 4.

  PMID: 23463579 BACKGROUND

• Wasserman BA, Wityk RJ, Trout HH 3rd, Virmani R. Low-grade carotid stenosis: looking beyond the lumen with MRI. Stroke. 2005 Nov;36(11):2504-13. doi: 10.1161/01.STR.0000185726.83152.00. Epub 2005 Oct 20.

  PMID: 16239630 BACKGROUND

• Gupta A, Baradaran H, Schweitzer AD, Kamel H, Pandya A, Delgado D, Dunning A, Mushlin AI, Sanelli PC. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke. 2013 Nov;44(11):3071-7. doi: 10.1161/STROKEAHA.113.002551. Epub 2013 Aug 29.

  PMID: 23988640 BACKGROUND

• McNally JS, Kim SE, Mendes J, Hadley JR, Sakata A, De Havenon AH, Treiman GS, Parker DL. Magnetic Resonance Imaging Detection of Intraplaque Hemorrhage. Magn Reson Insights. 2017 Mar 7;10:1-8. doi: 10.1177/1178623X17694150. eCollection 2017.

  PMID: 28469441 BACKGROUND

• Diagnostic Radiology: Magnetic Resonance Imaging (MRI) Practice Parameters and Technical Standards - American College of Radiology [Internet]. [cited 2015 Jan 30]. Available from: http://www.acr.org/Quality-Safety/Standards-Guidelines/Practice-Guidelines-by-Modality/MRI

  BACKGROUND

• de Havenon, A, Chung L, Park, M, Mossa-Basha, M. Intracranial vessel wall MRI: a review of current indications and future applications. Neurovascular Imaging. 2016;2(10).

  BACKGROUND

• Stroke Standards - NINDS Common Data Elements [Internet]. [cited 2015 Jan 3]. Available from: http://www.commondataelements.ninds.nih.gov/stroke.aspx#tab=Data_Standards

  BACKGROUND

• Mandell DM, Mossa-Basha M, Qiao Y, Hess CP, Hui F, Matouk C, Johnson MH, Daemen MJ, Vossough A, Edjlali M, Saloner D, Ansari SA, Wasserman BA, Mikulis DJ; Vessel Wall Imaging Study Group of the American Society of Neuroradiology. Intracranial Vessel Wall MRI: Principles and Expert Consensus Recommendations of the American Society of Neuroradiology. AJNR Am J Neuroradiol. 2017 Feb;38(2):218-229. doi: 10.3174/ajnr.A4893. Epub 2016 Jul 28.

  PMID: 27469212 BACKGROUND

• Scott McNally J, Yoon HC, Kim SE, Narra KK, McLaughlin MS, Parker DL, Treiman GS. Carotid MRI Detection of Intraplaque Hemorrhage at 3T and 1.5T. J Neuroimaging. 2015 May-Jun;25(3):390-6. doi: 10.1111/jon.12146. Epub 2014 Jul 15.

  PMID: 25040677 BACKGROUND

• van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, Inzitari D, Waldemar G, Erkinjuntti T, Mantyla R, Wahlund LO, Barkhof F; LADIS Group. Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke. 2006 Mar;37(3):836-40. doi: 10.1161/01.STR.0000202585.26325.74. Epub 2006 Jan 26.

  PMID: 16439704 BACKGROUND

• Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, Sullivan M, Horowitz KR, Ding J, Marcovina S, Lovato LC, Lovato J, Margolis KL, O'Connor P, Lipkin EW, Hirsch J, Coker L, Maldjian J, Sunshine JL, Truwit C, Davatzikos C, Bryan RN; ACCORD MIND investigators. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011 Nov;10(11):969-77. doi: 10.1016/S1474-4422(11)70188-0. Epub 2011 Sep 28.

  PMID: 21958949 BACKGROUND

• SNOMED Clinical Terms® (SNOMED CT®) [Internet]. [cited 2015 Jan 3]. Available from: http://www.nlm.nih.gov/research/umls/Snomed/snomed_main.html

  BACKGROUND

MeSH Terms

Conditions

Stroke; Intracranial Arteriosclerosis

Interventions

alirocumab

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Intracranial Arterial Diseases; Arteriosclerosis; Arterial Occlusive Diseases

Study Officials

• Adam de Havenon, MD

  University of Utah

  PRINCIPAL INVESTIGATOR

• Scott McNally, MD, PhD

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: April 13, 2018
• First Posted: April 25, 2018
• Study Start: October 30, 2018
• Primary Completion: April 17, 2020
• Study Completion: April 17, 2020
• Last Updated: April 21, 2020

Record last verified: 2020-04

Locations

US (1)