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Clinical Trial Design in Subjects with Intracerebral Hemorrhage

  • Adeola Olowu
  • Nicole R. Gonzales
Chapter

Abstract

Intracerebral hemorrhage results in the greatest morbidity and mortality compared to other types of stroke. Although advancements have been made in the management of intracerebral hemorrhage, currently, there is no effective treatment which improves outcomes. In order to develop treatment for intracerebral hemorrhage, efforts should be focused on better understanding of the pathophysiology of disease. In addition, consideration should be given to adapting clinical trial design to address the unique clinical challenges of this disease. These challenges include the acute nature and heterogeneity of disease, smaller number of patients compared with ischemic stroke, and difficulty in recruitment and retention, to name a few. The purpose of this chapter is to explore potential solutions to some of the challenges of designing clinical trials for patients with intracerebral hemorrhage.

Keywords

Intracerebral hemorrhage Stroke Clinical trial design Randomized controlled trial Informed consent Telemedicine Clinical research Treatment Adaptive design Regulatory guidelines Outcomes 

References

  1. 1.
    Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358(20):2127–37.CrossRefPubMedGoogle Scholar
  2. 2.
    Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355–65.CrossRefPubMedGoogle Scholar
  3. 3.
    Tuhrim S. Intracerebral hemorrhage – improving outcome by reducing volume? N Engl J Med. 2008;358(20):2174–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7(5):391–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Grotta JC, Albers G, Broderick JP, Kasner SE, Lo EH, Mendelow AD, et al. Stroke : pathophysiology, diagnosis, and management. 6th ed: Elsevier Inc; 2016. 1 online resource p.Google Scholar
  6. 6.
    Cheung K, Kaufmann P. Efficiency perspectives on adaptive designs in stroke clinical trials. Stroke. 2011;42(10):2990–4.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kenyon GM, Mendelow AD, Gregson BA, Rowan E. Obtaining regulatory approval for multicentre randomised controlled trials: experiences in the STICH II trial. Br J Neurosurg. 2011;25(3):352–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Jadad AR, Enkin M, Jadad AR. Randomized controlled trials: questions, answers, and musings. Blackwell Publishing; Malden, Massachusetts. 2nd ed. xxiv, 136 p.Google Scholar
  9. 9.
    Slyter H. Ethical challenges in stroke research. Stroke. 1998;29(8):1725–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Masuca SR, Das DS, Delano D, Irani M, Pandurengan R, Barreto AD, et al. Abstract 3769: barriers to obtaining informed consent in acute stroke clinical trials. Stroke. 2012;43(Suppl 1):A3769-A.Google Scholar
  11. 11.
    Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296–306.CrossRefPubMedGoogle Scholar
  12. 12.
    Stunkel L, Benson M, McLellan L, Sinaii N, Bedarida G, Emanuel E, et al. Comprehension and informed consent: assessing the effect of a short consent form. IRB. 2010;32(4):1–9.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Wu TC, Sarraj A, Jacobs A, Shen L, Indupuru H, Biscamp D, et al. Telemedicine-guided remote enrollment of patients into an acute stroke trial. Ann Clin Trans Neurol. 2015;2(1):38–42.CrossRefGoogle Scholar
  14. 14.
    Alfredo Caceres J, Greer DM, Goldstein JN, Viswanathan A, Suarez JI, Brau L, et al. Enrollment of research subjects through telemedicine networks in a multicenter acute intracerebral hemorrhage clinical trial: design and methods. J Vasc Intervent Neurol. 2014;7(3):34–40.Google Scholar
  15. 15.
    Switzer JA, Hall CE, Close B, Nichols FT, Gross H, Bruno A, et al. A telestroke network enhances recruitment into acute stroke clinical trials. Stroke. 2010;41(3):566–9.CrossRefPubMedGoogle Scholar
  16. 16.
    U.S. Department of Health and Human Services Food, Drug Administration Office of Good Clinical Practice Center for Drug Evaluation, Research Center for Biologics Evaluation, Research Center for Devices, Radiological Health. Guidance for institutional review boards. Clinical investigators, and sponsors; exception from informed consent requirements for emergency research. Washington, DC: U. S. Food and Drug Administration; 2013.Google Scholar
  17. 17.
    Bateman BT, Meyers PM, Schumacher HC, Mangla S, Pile-Spellman J. Conducting stroke research with an exception from the requirement for informed consent. Stroke. 2003;34(5):1317–23.CrossRefPubMedGoogle Scholar
  18. 18.
    Halperin H, Paradis N, Mosesso V Jr, Nichol G, Sayre M, Ornato JP, et al. Recommendations for implementation of community consultation and public disclosure under the Food and Drug Administration’s “Exception from informed consent requirements for emergency research”: a special report from the American Heart Association Emergency Cardiovascular Care Committee and Council on Cardiopulmonary, Perioperative and Critical Care: endorsed by the American College of Emergency Physicians and the Society for Academic Emergency Medicine. Circulation. 2007;116(16):1855–63.CrossRefPubMedGoogle Scholar
  19. 19.
    Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457–66.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Dickert NW, Scicluna VM, Baren JM, Biros MH, Fleischman RJ, Govindarajan PR, et al. Patients’ perspectives of enrollment in research without consent: the patients’ experiences in emergency research-progesterone for the treatment of traumatic brain injury study. Crit Care Med. 2015;43(3):603–12.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zaidat OO, Liebeskind DS, Edgell RC, Amlie-Lefond CM, Kalia JS, Alexandrov AV. Clinical trial design for endovascular ischemic stroke intervention. Neurology. 2012;79(13 Suppl 1):S221–33.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dorsey ER, Venuto C, Venkataraman V, Harris DA, Kieburtz K. Novel methods and technologies for 21st-century clinical trials: a review. JAMA Neurol. 2015;72(5):582–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet (London, England). 2010;375(9727):1695–703.CrossRefGoogle Scholar
  24. 24.
    Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30.CrossRefPubMedGoogle Scholar
  26. 26.
    Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18.CrossRefPubMedGoogle Scholar
  27. 27.
    Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–95.CrossRefPubMedGoogle Scholar
  28. 28.
    Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28(1):1.CrossRefPubMedGoogle Scholar
  29. 29.
    Flaherty M, Jauch E. Spot sign for predicting and treating ICH growth study (STOP-IT) [updated 6/2011]. Available from: http://clinicaltrials.gov/ct2/show/NCT00810888; NLM Identifier: NCT00810888.
  30. 30.
    Diringer MN, Edwards DF. Admission to a neurologic/neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage. Crit Care Med. 2001;29(3):635–40.CrossRefPubMedGoogle Scholar
  31. 31.
    Varelas PN, Schultz L, Conti M, Spanaki M, Genarrelli T, Hacein-Bey L. The impact of a neuro-intensivist on patients with stroke admitted to a neurosciences intensive care unit. Neurocrit Care. 2008;9(3):293–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Burns JD, Green DM, Lau H, Winter M, Koyfman F, DeFusco CM, et al. The effect of a neurocritical care service without a dedicated neuro-ICU on quality of care in intracerebral hemorrhage. Neurocrit Care. 2013;18(3):305–12.CrossRefPubMedGoogle Scholar
  33. 33.
    Jaffe J, AlKhawam L, Du H, Tobin K, O’Leary J, Pollock G, et al. Outcome predictors and spectrum of treatment eligibility with prospective protocolized management of intracerebral hemorrhage. Neurosurgery. 2009;64(3):436–45; discussion 45–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31(25):2973–84.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Albers GW, Bogousslavsky J, Bozik MA, Brass LM, Broderick JP, Fisher M, Goldstein LB, Salazar-Grueso E, Zivin JA, Akitsuki S, Aranko K, Ashwood T, Atkinson RP, Bell RD, Brott TG, Cady WJ, Caplan LR, Coggins S, Cramer S, Cyrus P, Dayno J, Donald Easton J, Elliott PJ, Finklestein SP, Furlan AJ, Gamzu E, Glasky MS, Gordon K, Gorelick PB, Greenwood DT, Grotta JC, Gunn K, Hachinski V, Hacke W, Hall ED, Hsu CY, Michael Humphreys D, Ishikawa H, Jacobs AJ, Kaste M, Koroshetz WJ, Krams M, Lauritano AA, Leclerc J, Lees KR, Lesko L, Levine SR, Levy DE, Li F, Lyden PD, Masayasu H, McDermott J, Meibach RC, Meya U, Miyairi K, Niidome T, Oeda J, Michael Poole R, Ron ES, Sacco RL, Saltarelli MD, Shimizu K, Shook BJ, Soehngen M, Soehngen W, Stamler DA, Styren SD, Teal PA, Tilley BC, Traystman RJ, Walker MD, Wallin BA, Warach S, Ward DP, Wessel TC, Wettstein J, Stroke Therapy Academic Industry Roundtable II (STAIR-II), Writing Committee. Recommendations for clinical trial evaluation of acute stroke therapies. Stroke. 2001;32(7):1598.Google Scholar
  36. 36.
    Saver JL, Gornbein J. Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology. 2009;72(15):1310–5.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Stafinski T, Menon D, Nardelli A, Bakal J, Ezekowitz J, Tymchak W, et al. Incorporating patient preferences into clinical trial design: results of the opinions of patients on treatment implications of new studies (OPTIONS) project. Am Heart J. 2015;169(1):122–31.e22.CrossRefPubMedGoogle Scholar
  38. 38.
    Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5(7):603–12.CrossRefPubMedGoogle Scholar
  39. 39.
    Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375(11):1033–43.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener H-C, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage. Stroke. 2007;38(8):2262.CrossRefPubMedGoogle Scholar
  41. 41.
    Baharoglu MI, Cordonnier C, Salman RA-S, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605–13.CrossRefPubMedGoogle Scholar
  42. 42.
    Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the international surgical trial in intracerebral haemorrhage (STICH): a randomised trial. Lancet (London, England). 2005;365(9457):387–97.CrossRefGoogle Scholar
  43. 43.
    Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013;382(9890):397–408.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hanley DF, CLEAR III Investigators. Clot lysis: evaluating accelerated resolution of intraventricular hemorrhage (CLEAR III) results. International stroke conference, 2016; Los Angeles California; Oral Abstract LB12. 2016.Google Scholar
  45. 45.
    Sangha N, Irani M, Peng H, Rahbar MH, Martinez R, Barreto AD, Savitz SI, Wu T, Lopez G, Misra V, Ifejika N, Grotta JC, Gonzales NR. Longitudinal assessment of functional outcome in intracerebral hemorrhage. European stroke conference, Lisbon. 2012(Abstract #330).Google Scholar
  46. 46.
    The Specifications Manual for Joint Commission National Quality Measures (Version 2016A1) is periodically updated by The Joint Commission.Google Scholar
  47. 47.
    Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032–60.CrossRefPubMedGoogle Scholar
  48. 48.
    Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5(1):53–63.CrossRefPubMedGoogle Scholar
  49. 49.
    Gonzales NR. Ongoing clinical trials in intracerebral hemorrhage. Stroke. 2013;44(6 suppl 1):S70.CrossRefPubMedGoogle Scholar
  50. 50.
    Augustine EF, Dorsey ER, Hauser RA, Elm JJ, Tilley BC, Kieburtz KK. Communicating with participants during the conduct of multi-center clinical trials. Clinl Trials (London, England). 2016;13:592.CrossRefGoogle Scholar
  51. 51.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry: adaptive design clinical trials for drugs and biologics. 2010. www.fda.gov/downloads/Drugs/.../Guidances/ucm201790.pdf on 11/20/16.
  52. 52.
    Rahbar MH, Dickerson AS, Cai C, Pedroza C, Hessabi M, Shen L, et al. Methodological issues for designing and conducting a multicenter, international clinical trial in acute stroke: experience from ARTSS-2 trial. Contemp Clin Trials. 2015;44:139.CrossRefPubMedGoogle Scholar
  53. 53.
    Connor JT, Broglio KR, Durkalski V, Meurer WJ, Johnston KC. The stroke hyperglycemia insulin network effort (SHINE) trial: an adaptive trial design case study. Trials. 2015;16:72.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Elkind MS, Sacco RL, Macarthur RB, Peerschke E, Neils G, Andrews H, et al. High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART). Cerebrovasc Dis (Basel, Switzerland). 2009;28(3):266–75.CrossRefGoogle Scholar
  55. 55.
    Gonzales NR, Shah J, Sangha N, Sosa L, Martinez R, Shen L, et al. Design of a prospective, dose-escalation study evaluating the safety of pioglitazone for hematoma resolution in intracerebral hemorrhage (SHRINC). Int J Stroke Off J Int Stroke Soc. 2013;8(5):388–96.CrossRefGoogle Scholar
  56. 56.
    Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, et al. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke. 2010;41(10):2283–7.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Grieve AP, Krams M. ASTIN: a Bayesian adaptive dose-response trial in acute stroke. Clin Trials, (London, England). 2005;2(4):340–51; discussion 52–8, 64–78.CrossRefGoogle Scholar
  58. 58.
    Howard G. Nonconventional clinical trial designs: approaches to provide more precise estimates of treatment effects with a smaller sample size, but at a cost. Stroke. 2007;38(2 Suppl):804–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Holford NH, Kimko HC, Monteleone JP, Peck CC. Simulation of clinical trials. Annu Rev Pharmacol Toxicol. 2000;40:209–34.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyMcGovern Medical SchoolHoustonUSA

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