Desmoteplase for acute ischaemic

September 2011

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

September 2011

Desmoteplase for acute ischaemic stroke

Target group • Acute ischaemic stroke – within 3 to 9 hours of the onset of symptoms.

Technology description Desmoteplase (LU-AE-03329) is a recombinant fibrin-specific derived from the saliva of the vampire bat, Desmodus rotundus. It catalyses the conversion of plasminogen to , the enzyme responsible for breaking down fibrin blood clots. Structurally, desmoteplase is very similar to human tissue-type plasminogen activator (tPA), but its activity is 200 times more fibrin-specific than tPA. It therefore does not cause systemic plasminogen activation and fibrinogen depletion. Desmoteplase is intended to be used for the treatment of patients with acute ischaemic stroke in the extended time window of 3 to 9 hours after the onset of symptoms. It is administered as an IV bolus at 90µg/kg (dose used in ongoing phase III clinical trials).

Innovation and/or advantages If licensed, desmoteplase would extend the time window for in acute stroke from 3 hours to 9 hours. In addition, because it is highly fibrin-specific it may not have some of the negative effects of tPA (like systemic plasminogen activation and neurotoxicity).

Developer Lundbeck.

Availability, launch or marketing dates, and licensing plans In phase III clinical trials.

NHS or Government priority area This topic is relevant to Equity and Excellence: Liberating the NHS (2010); The National Stroke Strategy (2007); The National Service Framework for Older People (2001) and The National Service Framework for Coronary Heart Disease (2000).

Relevant guidance • NICE technology appraisal. for the treatment of acute ischaemic stroke. 2007 (review April 2010)1. • NICE clinical guideline in development. Rehabilitation after stroke. Expected April 20122. • NICE clinical guideline. Stroke: the diagnosis and acute management of stroke and transient ischaemic attacks (TIA). 20083.

• University of Warwick and Joint Royal Colleges Ambulance Liaison Committee care guideline. Stroke/transient ischaemic attack (TIA) - updated guidance. 20094. • SIGN. Management of patients with stroke or TIA: assessment, investigation, immediate management and secondary prevention. 20085. • The Royal College of Physicians. National clinical guideline for stroke, 3rd edition. 20086. • American College of Chest Physicians Evidence-Based clinical practice guideline. and thrombolytic therapy for ischemic stroke. 20087.

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• American Heart Association/American Stroke Association Stroke Council. Guidelines for the early management of adults with ischemic stroke. 20078.

Clinical need and burden of disease Acute ischaemic stroke is usually caused by cerebral artery thrombosis or embolism, and accounts for 85% of all strokes9, with the remaining 15% being due to intracranial haemorrhage4. Men are at greater risk of stroke than women, and 75% of occur in people aged 65 or over9.

Stroke is the third most common cause of death in England and Wales, and the leading cause of severe disability10. Each year in England and Wales, approximately 130,000 people have a first or recurrent stroke11. The risk of recurrent stroke within five years of a first stroke is between 30% and 43%6. In 2009-10, there were 90,822 emergency cases of stroke (ICD10 I60-I64) and 182,944 finished consultant episodes recorded in England12. Following a stroke, approximately 23% of people die within 30 days3, and of initial stroke survivors only 30%-40% are alive after 3 years13. Stroke accounted for 31,613 deaths in England and Wales in 2009 (ICD10 I60-I64)14. More than 900,000 people in England are living with the effects of stroke, with half of these being dependent on other people for help with everyday activities3.

A UK study found that 37% of stroke patients presented to hospital within 3 hours of symptom onset15. The median time from stroke to first brain imaging (required to exclude intracranial haemorrhage) is 27 hours in the UK, with fewer than half of patients undergoing brain imaging within 24 hours of symptom onset, and only 15% of patients are admitted to a specialist stroke unit on the same day as their stroke occurs16.

The annual cost of stroke in the England has been estimated at around £7 billion3. This comprises direct costs to the NHS of £2.8 billion, costs of informal care of £2.4 billion, and costs because of lost productivity and disability of £1.8 billion3.

Existing comparators and treatments Standard pharmacological treatment for acute ischaemic stroke include thrombolytic therapy with alteplase within 3 hours of symptom onset and anti-platelet treatment with , as soon as possible and within 24 hours of symptom onset1,3. Alternative antiplatelet agents, such as clopidrogel or modified-release , are given if the person with acute ischaemic stroke is allergic or intolerant to aspirin3,13. Alteplase is not indicated for children under 18 years, or adults over 80 years1 and thrombolytic therapy is associated with a risk of bleeding complications, the most important of which being haemorrhagic stroke (occurring in 0.5 to 6.0% of patients3,17), resulting in high mortality and long-term disability among survivors.

Efficacy and safety

Trial DIAS-4, NCT00856661, 12649A; DIAS-3, NCT00790920, 12402A; desmoteplase or placebo; phase III. desmoteplase or placebo; phase III. Sponsor H. Lundbeck A/S. H. Lundbeck A/S. Status Ongoing. Ongoing. Source of Trial registry18. Trial registry19. information Location EU (inc UK), USA, Canada and other EU, South East Asia and Western Pacific. countries. 3 September 2011

Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=400 (planned); adults; acute ischaemic n=400 (planned); adults; acute ischaemic and schedule stroke; NIHSS scorea 4-24; treatment stroke; NIHSS score 4-24; treatment within 3-9 hrs of symptom onset; vessel within 3-9 hrs of symptom onset; vessel occlusion or high grade stenosis in occlusion or high grade stenosis in proximal cerebral arteries; not treated proximal cerebral arteries; not treated with thrombolytic agent, or with thrombolytic agent, heparin or inhibitors of glycoprotein IIb-IIa (except inhibitors of glycoprotein IIb-IIa (except single oral platelet inhibitors like aspirin) single oral platelet inhibitors like aspirin) in the past 72, 48 and 72 hrs respectively; in the past 72, 48 and 72 hrs respectively; not on treatment with oral ; not on treatment with oral anticoagulants; normal prothrombin and/or partial normal prothrombin and/or partial thromboplastin time. thromboplastin time. Randomised to desmoteplase 90µg/kg or Randomised to desmoteplase 90µg/kg or placebo. placebo. Follow-up Received treatment within 3-9 hrs of onset Received treatment within 3-9 hrs of onset of stroke symptoms, then 90 days follow of stroke symptoms, then 90 days follow up. up. Primary Modified Rankin Scale (mRS) score. mRS score. outcome/s Secondary NIHSS score. NIHSS score. outcome/s Expected Study expected to complete July 2012. Study expected to complete September reporting date 2011.

Trial DIAS-2, NCT00111852, DSP-MD-01; DIAS, NCT00638781, PN01-CLD- desmoteplase or placebo; phase III. 000001/01; desmoteplase or placebo; phase II. Sponsor Forest Laboratories. PAION Deutschland GmbH. Status Published. Published. Source of Publication20, trial registry21. Publication22, trial registry23. information Location EU, USA, Canada, Australia and EU (inc UK), Australia and Singapore. Singapore. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=193; adults; acute ischaemic stroke; n=104 (47 in part 1, 57 in part 2); adults; and schedule NIHSS score 4-24; treatment within 3-9 acute ischaemic stroke; NIHSS score 4- hrs of symptom onset; clinical signs of 20; treatment within 3-9 hrs of symptom cerebral hemispheric infarction; ≥ 20% onset; ≥ 20% perfusion/diffusion penumbra; received study medication mismatch involving hemispheric grey within 60 mins of diagnostic imaging; not matter; treated within 30 mins of MRI; treated with heparin (except low dose SC not on treatment with inhibitors of platelet heparin) or inhibitors of glycoprotein IIb- function. IIa (except single oral platelet inhibitors Part 1: randomised to desmoteplase at like aspirin) in the past 48 and 72 hrs 25mg, 37.5mg, 50mg or placebo. After respectively; not on treatment with oral enrolment of 30th patient, 37.5 and 50mg anticoagulants; normal prothrombin arms discontinued due to occurrence of and/or partial thromboplastin time. symptomatic ICH. Trial halted after Randomised to desmoteplase 90µg/kg, recruitment of 47th patient due to high 125µg/kg or placebo. symptomatic ICH rates in 25mg arm. Part 2: randomised to desmoteplase a NIHSS – National Institute of Health stroke scale, a 15-item neurologic examination scale used to evaluate the effect of acute cerebral infarction on levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. 4 September 2011

62.5µg/kg, 90µg/kg, 125µg/kg or placebo. Follow-up Received treatment within 3-9 hrs of onset Received treatment within 3-9 hrs of onset of stroke symptoms, then 90 days follow of stroke symptoms, then 90 days follow up. up. Primary Clinical improvement at day 90, Reperfusion; clinical improvement at day outcome/s (improvement in NIHSS of ≥8 points or 90 (improvement in NIHSS of ≥8 points NIHSS ≤1 point, mRS score of 0-2 and or NIHSS ≤1 point, mRS score of 0-2 and Barthel index (BI) of 75-100); BI of 75-100); symptomatic ICH. symptomatic intracranial haemorrhage (ICH). Secondary Infarct volume at day 30; clinical response Infarct volume at day 30; major systemic outcome/s on individual components of primary bleeding; anaphylaxis; mortality. endpoint at day 90; mortality. Key results At day 90 for placebo, desmoteplase Reperfusion [ %, [95% CI], p value vs 90µg/kg and 125µg/kg respectively: placebo] 4-8 hrs after treatment for: clinical improvement, 46%, 47%, 36%, Part 1- placebo, 18.8%, [4.0, 45.6]; p=0.47 (desmoteplase vs placebo); NIHSS desmoteplase 25mg, 56.3%, [29.9, 80.2], ≤1 or improvement ≥8 points, 59%, 58%, p=0.0086; desmoteplase 37.5/50mg, 50%; mRS score 0-2, 57%, 54%, 49%; 46.2%, [19.2, 74.9], p=0.0431. BI 75-100, 67%, 68%, 55%. Part 2 - placebo, 20.0%, [2.5, 55.6]; desmoteplase 62.5µg/kg, 23.1%, [5.0, 53.8], p=0.389; desmoteplase 90µg/kg, 46.7%, [21.3, 73.4], p=0.0349; desmoteplase 12.5µg/kg, 71.4%, [41.9, 91.6], p=0.0012. Total - placebo, 19.2%, [6.6, 39.4]; desmoteplase, 49.3%, [37.2, 61.4], p=0.0054; both groups combined, 41.2%, [31.3, 51.7]. Adverse Most common AEs included ischaemic For placebo and desmoteplase effects (AEs) stroke (11%), pneumonia (7%), decreased respectively: haemoglobin (6%) and ICH (5%). Part 1: symptomatic ICH within 25 hrs of For placebo, desmoteplase 90µg/kg and treatment, 0%, 26.7%; asymptomatic ICH, 125µg/kg respectively: 12.5%, 16.7%; major gastrointestinal (GI) serious AEs, 29%, 35%, 36%; haemorrhage, n=1, n=2 (desmoteplase symptomatic ICH within 72 hrs of 25mg); death within 90 days, n= 0, n=7. treatment, 0, 3.5%, 4.5%; asymptomatic Part 2: symptomatic ICH, 0%, 2.2% ICH within 72 hrs of treatment, 33%, (desmoteplase 90µg/kg); asymptomatic 35%, 33%; death within 90 days, n=4, ICH, 27.3%, 31.1%. Major GI n=3, n=14. haemorrhage, n=0, n=1 (desmoteplase 62.5µg/kg).

Trial DIAS-J, NCT01104467, 11764A; DEDAS, NCT00638248, PN01-CLD- desmoteplase or placebo; phase II. 000002/01; desmoteplase or placebo; phase I/II. Sponsor Lundbeck Japan K.K. PAION Deutshland GmbH. Status Ongoing. Published. Source of Trial registry24. Publication25, trial registry26. information Location Japan. USA and Germany. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=48 (planned); adults; acute ischaemic n=37; adults; acute ischaemic stroke; and schedule stroke; NIHSS score 4-24; treatment enrolment within 3-9 hrs of symptoms within 3-9 hrs symptoms onset; vessel onset; NIHSS score 4-20; ≥ 20% occlusion or high grade stenosis in middle perfusion-difussion mismatch, with or 5 September 2011

cerebral arteries; received study without perfusion-weighted/diffusion- medication within 60 mins of diagnostic weighted lesion of >2cm and involving imaging; not treated with thrombolytic cerebral cortex. agent and heparin in the past 72 and 48 Randomised to desmoteplase at 90µg/kg, hrs respectively; not on treatment with 125µg/kg or placebo. oral anticoagulants; normal prothrombin and/or partial thromboplastin time. Randomised to desmoteplase at 70µg/kg, 90µg/kg or placebo. Follow-up Received treatment within 3-9 hrs of onset Received treatment within 3-9 hrs of of stroke symptoms, then 90 days follow onset of stroke symptoms, then 90 days up. follow up. Primary Symptomatic ICH within 72 hrs of Good clinical outcome at day 90 outcome/s receiving study medication. (improvement in NIHSS of ≥8 points or NIHSS ≤1 point, mRS score of 0-2 and BI of 75-100); reperfusion at 4-8 hrs; symptomatic ICH. Secondary mRS score at days 7, 30 and 90; Safety outcomes including mortality, outcome/s recanalisation and change in infarct size at anaphylaxis and major systemic 18±6 hrs after administration of study bleeding. medication; pharmacokinetics, pharmacodynamics and immunogenicity of desmoteplase; predictive value of different volumes of absolute mismatch for clinical response and other objectives. Key results - Reperfusion [%, [95% CI], p value vs placebo] 4-8 hrs after treatment for: ITTb analysis - placebo, 37.5%, [8.5, 75.5]; desmoteplase 90µg/kg, 18.2%, [2.3, 51.8], p=0.82; desmoteplase 125µg/kg, 53.3%, [26.6, 78.7], p=0.24. TPc - placebo, 33.3%, [4.3, 77.7]; desmoteplase 90µg/kg, 16.7%, [0.4, 64.1], p=0.74; desmoteplase 125µg/kg, 63.6%, [30.8, 89.1], p=0.12.

Good clinical outcome [%, [95% CI], p value vs placebo] at day 90 for: ITT analysis - placebo, 25.0%, [3.2, 65.1]; desmoteplase 90µg/kg, 28.6%, [8.4, 58.1], p=0.43; desmoteplase 125µg/kg: 60.0%, [32.3, 83.7], p=0.061. TP - placebo, 16.7%, [0.4, 64.1]; desmoteplase 90µg/kg, 37.5%, [8.5, 75.5], p=0.20; desmoteplase 125µg/kg, 72.7%, [39.0, 94.0], p=0.022.

69% (9/13) of patients with reperfusion had a good clinical outcome compared with 19% (4/21) without reperfusion (p=0.003).

b ITT- intention to treat. c TP- target population. TP included 25 patients who had MRI mismatch and no isolated internal carotid occlusion. 6 September 2011

Expected Study expected to complete December - reporting date 2011. Adverse - No symptomatic ICHs and anaphylactic effects (AEs) reactions were observed. Death within 90 days occurred in 1 patient in each group. For placebo, desmoteplase 90µg/kg and 125µg/kg respectively: asymptomatic ICH, 12.5%, 35.7%, 40%; major systemic haemorrhage, 12.5%, 14.3%, 13.3%.

Estimated cost and cost impact The cost of desmoteplase is not yet known.

Claimed or potential impact – speculative Patients Reduced mortality or increased  Reduction in associated Quicker, earlier or more accurate length of survival morbidity or Improved quality of diagnosis or identification of life for patients and/or carers disease Other: None identified

Services  Increased use: new treatment Service organisation Staff requirements option up to 9 hrs after symptom onset.

 Decreased use: potential for Other: None identified reduced disability.

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed  New costs: new treatment option.  Savings: may reduce the risk of Other: recurrent stroke.

Other issues  Clinical uncertainty or other research question identified: None identified Services may need to adopt rapid access to relevant imaging and specialist stroke facilities to enable rapid assessment and delivery of therapy. The best imaging modality to be used for patient selection for therapy has not yet been established. Data on the effects of desmoteplase on long term outcomes like disability, recurrent strokes is required.

References

1 National Institute for Health and Clinical Excellence. Alteplase for the treatment of acute ischaemic stroke. Technology appraisal TA122. London: NICE; June 2007 (review date April 2010). 2 National Institute for Health and Clinical Excellence. Rehabilitation after stroke. NICE clinical guideline in development. Expected April 2012. 3 National Institute for Health and Clinical Excellence. Stroke: the diagnosis and acute management of stroke and transient ischaemic attacks. Clinical guideline CG68. London: NICE; July 2008. 4 University of Warwick and Joint Royal Colleges Ambulance Liaison Committee. Stroke/transient ischaemic attack (TIA). Care guideline. University of Warwick and Joint Royal Colleges Ambulance Liaison Committee, Warwick; September 2009.

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5 Scottish Intercollegiate Guidelines Network. Management of patients with stroke or TIA: assessment, investigation, immediate management and secondary prevention. National clinical guideline 108. Edinburgh: SIGN; December 2008. 6 Intercollegiate Stroke Working Party. National clinical guideline for stroke, 3rd edition. London: Royal College of Physicians; July 2008. 7 Albers GW, Amarenco P, Easton JD et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6):630S-669S. 8 Adams HP Jr, del Zoppo G, Alberts MJ et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology. Stroke 2007;38(5):1655-1711. 9Cruz-Flores S, Arnold JL, Becker JU et al. Ischemic Stroke in Emergency Medicine. http://emedicine.medscape.com/article/1916852-overview Accessed 5 August 2011. 10 The Stroke Association. Facts and figures about stroke. http://www.stroke.org.uk/media_centre/facts_and_figures/index.html Accessed 5 August 2011. 11 National Institute for Health and Clinical Excellence. Final scope for the appraisal of for the prevention of stroke and systemic embolism in people with atrial fibrillation. London: NICE; June 2011. 12NHS. Hospital episode statistics. NHS England 2009-2010 inpatient data. HES data 2010. www.hesonline.nhs.uk 13 National Institute for Health and Clinical Excellence. and modified-release dipyridamole for the prevention of occlusive vascular events. Technology appraisal TA210. London: NICE; December 2010. 14Office for National Statistics. Mortality statistics-deaths registered in 2009. http://www.statistics.gov.uk/downloads/theme_health/dr2009/dr-09.pdf 15 Harraf F, Sharma A, Brown M et al. A multicentre observational study of presentation and early assessment of acute stroke. British Medical Journal 2002;325:17-21 16 Clinical effectiveness and evaluation unit, Royal College of Physicians of London. National Sentinel Stroke Audit phase 2. London: Royal College of Physicians; 2007. 17 National Institute for Health and Clinical Excellence. Guidance on the use of thrombolysis in the treatment of acute myocardial infarction. Technology appraisal TA52. London: NICE; October 2002. 18 ClinicalTrials.gov. Efficacy and safety study of desmoteplase to treat acute ischemic stroke (DIAS-4). http://clinicaltrials.gov/ct2/show/NCT00856661? Accessed 5 August 2011. 19ClinicalTrials.gov. Efficacy and safety study of desmoteplase to treat acute ischemic stroke (DIAS-3). http://clinicaltrials.gov/ct2/show/NCT00790920? Accessed 5 August 2011. 20 Hacke W, Furlan AJ, Al-Rawi Y et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion–diff usion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurology 2009;8:141-50. 21 ClinicalTrials.gov. Study of desmoteplase (International Nonproprietary Name [INN]) in acute ischemic stroke (DIAS-2). http://clinicaltrials.gov/ct2/show/NCT00111852? Accessed 5 August 2011. 22 Hacke W, Albers G, Al-Rawi Y et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS) : A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase. Stroke 2005;36:66-73. 23ClinicalTrials.gov. Desmoteplase in acute ischemic stroke (DIAS). http://clinicaltrials.gov/ct2/show/NCT00638781? Accessed 5 August 2011. 24 ClinicalTrials.gov. Clinical study of desmoteplase in japanese patients with acute ischemic stroke (DIAS-J). http://clinicaltrials.gov/ct2/show/NCT01104467? Accessed 5 August 2011. 25 Furlan AJ, Eyding D, Albers GW et al. dose escalation of desmoteplase for acute ischemic stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37:1227-1231. 26ClinicalTrials.gov. Dose escalation of desmoteplase in acute ischemic stroke (DEDAS). http://clinicaltrials.gov/ct2/show/NCT00638248? Accessed 5 August 2011.

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