October Horizon Scanning Research & 2016 Intelligence Centre

Intepirdine for Alzheimer’s disease – add on therapy

NIHR HSRIC ID: 3668

Lay summary

Intepirdine is a new drug to treat Alzheimer’s disease in people with mild to moderate symptoms. Intepirdine is taken by mouth with , a drug that is already used in some patients with Alzheimer’s disease. Intepirdine causes the release of chemicals in the brain which may improve cognition and function. At the moment, there are no drugs that treat the underlying problem that causes Alzheimer’s disease and no known cure.

This briefing 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 or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Alzheimer’s disease (AD): mild to moderate – add on therapy; in combination with donepezil.

TECHNOLOGY

DESCRIPTION

Intepirdine (RVT-101; SB-742457; GSK 742457) is a 6 which causes the release of acetylcholine and other neurotransmitters that may improve cognition and function in AD. It is intended to be used in addition to donepezil, an acetylcholinesterase inhibitor. In the phase III clinical trial, intepirdine is administered orally at 35mg once daily for 24 weeks in combination with donepezil1.

Intepirdine does not currently have Marketing Authorisation in the EU for any indication. Intepirdine is in phase II clinical trials for with Lewy bodies.

INNOVATION and/or ADVANTAGES

If licensed, intepirdine will offer an additional treatment option for mild to moderate AD.

DEVELOPER

Axovant Sciences Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Dementia is a chronic progressive mental disorder, which is largely irreversible and characterised by a widespread impairment of mental function2,3. It adversely affects higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement. AD is the most common form of dementia. It is a degenerative cerebral disease with characteristic neuropathological and neurochemical features3.

AD is usually insidious in onset and develops over several years. People with AD may find it increasingly difficult to undertake everyday activities such as shopping, socialising, communication, and recognising people and places. In the later stages of the disease, physical impairments can include problems with eating (including dysphagia), incontinence, unsettled behaviour, and behaviour that challenges. AD may also be associated with loss of confidence and feelings of fear, confusion, apathy, stigma and depression. The effects of AD are heterogeneous and vary from patient to patient3.

Horizon Scanning Research & Intelligence Centre

A common tool to measure cognitive functioning is the mini mental state examination (MMSE)4. The MMSE is scored out of 30. Although scores of 24 or less are strongly associated with dementia in an appropriate clinical context, scores of >24 can be seen in some people with mild dementia. A score of ≥20 suggests mild dementia, 13 – 20 suggests moderate dementia, and ≤12 indicates severe dementia. On average, the MMSE score of a person with Alzheimer's declines about two to four points each year5.

CLINICAL NEED and BURDEN OF DISEASE

The number of people with dementia in the UK is estimated to be 850,000, representing 1.3% of the UK population6,7. AD accounts for around 60% of all dementia cases3,8. The UK incidence of AD in people over the age of 65 years was an estimated 4.9 per 1,000 person- years in 20113. Approximately 64% of people with AD are estimated to have mild to moderate disease3.

In 2014-15, there were 4,866 hospital admissions in England due to AD (ICD-10 G30), resulting in 9,364 finished consultant episodes and 318,152 bed days9. Expert opinion suggests the number of hospital admissions related to Alzheimer’s disease may be higher than this figure as many patients are admitted for a different reason but AD is a significant factora. Expert opinion also suggests that AD is associated with longer durations of hospital stay and, for many diseases, worse outcomesb. In 2014 in England and Wales, 11,298 deaths were registered in which Alzheimer’s disease was the underlying cause of death (ICD-10 G30)10.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Donepezil, , and for the treatment of Alzheimer's disease (TA217). March 2011.

• NICE clinical guideline in development. Dementia - assessment, management and support for people living with dementia and their carers (CG42 update). Expected September 2017. • NICE clinical guideline. Dementia: Supporting people with dementia and their carers in health and social care (CG42). November 2006

• NICE guideline. Older people: independence and mental wellbeing (NG32). December 2015. • NICE guideline. Older people with social care needs and multiple long-term conditions (NG22). November 2015. • NICE guideline. Dementia, disability and frailty in later life – mid-life approaches to delay or prevent onset (NG16). October 2015.

• NICE quality standard. Mental wellbeing of older people in care homes (QS50). December 2013.

a Expert personal opinion

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• NICE quality standard. Quality standard for supporting people to live well with dementia (QS30). April 2013. • NICE quality standard. Dementia quality standard (QS1). June 2010.

• NICE advice. Management of aggression, agitation and behavioural disturbances in dementia: valproate preparations (ESUOM41). March 2015. • NICE advice. Management of aggression, agitation and behavioural disturbances in dementia: carbamazepine (ESUOM40). March 2015. • NICE advice. Low-dose antipsychotics in people with dementia (KTT7). January 2015.

NHS England Policies and Guidance

• NHS England. Enhanced Service Specification: facilitating timely diagnosis and support for people with dementia 2015/16. • NHS England. Dementia diagnosis and management. A brief pragmatic resource for general practitioners. February 2015. • NHS commissioning Board. Commissioning for quality and innovation (CQUIN): Improving dementia and delirium care. February 2015. • NHS England. 2013/14 NHS standard contract for neurosciences: specialised neurology (Adult). D04/S/a. • NHS England. 2013/14 NHS standard contract for complex disability equipment: alternative and augmentative communication/communication aids (all ages). DO1/S/b.

Other Guidance

• NHS Clinical Knowledge Summary. Dementia. 201611. • European Federation of Neurological Societies. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. 201012. • British Association of Psychopharmacology. Clinical practice with anti-dementia drugs. 201013. • European Medicines Agency. Guideline on medicinal products for the treatment of Alzheimer’s disease and other . 200814. • Scottish Intercollegiate Guidelines Network. Management of patients with dementia (86). 200615.

CURRENT TREATMENT OPTIONS

There is currently no disease modifying treatment for AD. Treatment aims to promote independence, maintain function, and treat symptoms, including non-cognitive (such as hallucinations, delusions, anxiety, marked agitation and associated aggressive behaviour), cognitive, behavioural, and psychological symptoms2. Non-pharmacological management options include: cognitive stimulation, social support, increasing assistance with day-to-day activities, information and education, carer support groups, community dementia teams, home nursing and personal care, community services (such as meals-on-wheels), befriending services, day centres, respite care and care homes2,3. Pharmacological options for mild to moderate AD include acetylcholinesterase inhibitors such as donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate antagonist memantine. These drugs can temporarily reduce some symptoms of the condition in some people6,b.

b Expert personal opinion

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EFFICACY and SAFETY

Trial MINDSET Study, NCT02585934, RVT- MINDSET extension, NCT02586909, 101-3001; interpirdine vs placebo, both in RVT-101-3002; interpirdine in combination with donepezil; phase III. combination with donepezil; phase III extension. Sponsor Axovant Sciences Ltd. Axovant Sciences Ltd. Status Ongoing. Ongoing. Source of Trial registry1, manufacturer. Trial registry16, manufacturer. information Location EU (incl UK), USA, Canada and Australia. USA. Design Randomised, placebo-controlled. Open label. Participants n=1150 (planned); aged 50-85 yrs; n=1150 (planned); aged 50-85 yrs; pts Alzheimer’s disease (AD); receiving that have completed last on-treatment ongoing donepezil therapy for AD; mini– visit of the MINDSET study. mental state examination (MMSE) score 12-24 at screening; Hachinski Ischaemia score ≤4 at screening; reliable caregiver to report on status; no vascular dementia; no other forms of dementia; no history of significant psychiatric illness. Schedule Randomised to intepirdine 35mg oral Pts receive intepirdine 35mg oral once once daily; or placebo oral once daily; daily. both in combination with 5mg or 10mg donepezil.

Follow-up Active treatment for 24 wks, follow-up 24 Active treatment for 52 weeks, follow-up wks. 52 weeks. Primary Alzheimer's disease assessment scale - Adverse events; changes in physical outcomes cognitive subscale 11 items (ADAS-Cog- examinations, vital sign measurements, 11) score; Alzheimer's disease electrocardiograms (ECGs) or routine cooperative study - activities of daily living laboratory assessments. (ADCS-ADL) scale score. Secondary Clinical global impression of change - RUD Lite, Dependence Scale. outcomes plus caregiver input (CIBIC+); neuropsychiatric inventory (NPI) total score; EQ-5D Visual Analogue Scale (EQ-5D-VAS); adverse events (AEs); changes in clinical examinations, ECGs and routine laboratory assessments; resource utilisation in dementia (RUD) Lite, Dependence Scale. Expected Study completion date reported as Study completion date reported as June reporting October 2017. 2018. date

Trial NCT00710684, NCT00708552, NCT00224497, AZ3110866; intepirdine vs AZ3110865; interpirdine vs AZ3100603; interpirdine vs placebo, both in donepezil vs placebo; placebo; phase II. combination with phase II. donepezil; phase II. Sponsor GlaxoSmithKline. GlaxoSmithKline. GlaxoSmithKline. Status Published. Published. Published. Source of Publication17, trial Publication17, trial Publication20, trial information registry18, manufacturer. registry19, manufacturer. registry21, manufacturer.

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Location EU (not UK), USA, EU (not UK), Russian EU (not UK), Chile, Canada, Argentina, Federation, Mexico, Republic of Korea, New Australia and Chile. Republic of Korea and Zealand, Russian Chile. Federation, South Africa. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled, active- controlled. controlled. Participants n=684; aged 50-85 yrs; n=576; aged 50-85 yrs; n=371; aged 50-85 yrs; probable mild-to-moderate probable mild-to-moderate probable mild-to-moderate Alzheimer's disease; ≥6 Alzheimer's disease; a Alzheimer's disease as mnths of donepezil therapy regular caregiver to determined by the with stable dosing for at oversee compliance and NINCDS-ADRDA and least 2 mnths; a regular report on status; no DSM-IV criteria with an caregiver to oversee vascular dementia; no MMSE score of 12-26; no compliance and report on other CNS disorder that other causes of dementia status; no vascular could be interpreted as a such as vascular damage, dementia; no cause of dementia; no depression, bipolar hypersensitivity to sunlight; history of seizures, loss of affective disorder, no history of seizures. consciousness or schizophrenia, syphilis, significant head trauma; no vitamin B12 deficiency or photosensitivity. thyroid deficiency; no known hypersensitivity to sunlight or seizures. Schedule Randomised to intepirdine Randomised to intepirdine Randomised to intepirdine 15mg or 35mg oral; or 15mg or 35mg oral once 5mg, 15mg or 35mg oral; placebo; all once daily and dailey; placebo; or or placebo. in combination with donepezil (5-10mg). donepezil (5-10mg). Follow-up Active treatment for 48 Active treatment 24 wks, Active treatment 24 wks, wks, follow-up 48 wks. follow-up 24 wks. follow-up 24 wks. Primary Cognition and function Cognition and function. Cognition and function. outcomes measured using the ADAS-Cog score; CIBIC+ ADAS-Cog score; CIBIC+ Alzheimer’s disease score. score. assessment scale- cognitive subscale (ADAS-Cog) score; Clinical Dementia Rating-Sum of Boxes (CDR-SB). Secondary Safety and tolerability; Safety and tolerability; Behavioural symptoms; outcomes pharmacokinetics and pharmacokinetics and activities of daily living exploratory exploratory (ADL); caregiver burden; pharmacogenetics; ADCS- pharmacogenetics. ADCS- safety and tolerability; PK ADL; Repeatable Battery ADL; RBANS; MMSE; and dose response for Assessment of Cornell scale for profiling; efficacy related to Neuropsychological Status depression in dementia. apolipoprotein E (ApoE) (RBANS); MMSE. No quality of life status; NPI; disability No quality of life measurement included in assessment for dementia measurement included in trial outcomes. (DAD); MMSE; Alzheimer’s trial outcomes. carer’s quality of life instrument (ACQLI). Key results At wk 48: At wk 24: At wk 24: ADAS-Cog – a statistically ADAS-Cog – no significant ADAS-Cog – no significant significant improvement differences with difference with intepirdine with intepirdine 35mg vs intepirdine 35 mg or 15 35mg vs. placebo. placebo (difference of 1.6 mg, or donepezil vs. CIBIC+ - a statistically points, P=0.024). placebo. significant improvement CDR-SB - no statistically CIBIC+ - no statistically with intepirdine 35mg vs significant difference. significant differences placebo (p=0.047).

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ADCS-ADL – a non- observed with intepirdine statistically significant vs. placebo. increase with intepirdine MMSE – no statistically 35mg vs. placebo significant differences with (p= 0.088). intepirdine vs. placebo. RBANS and MMSE - no ADCS-ADL, RBANS, significant differences vs CSDD – no statistically placebo. differences for intepirdine, placebo or donepezil. Adverse Cumulative incidence of On-treatment AEs reported On-treatment AEs reported effects on-treatment AEs 60% at by 33% of subjects, similar by 30% of subjects. The (AEs) wk 48, proportion reporting across the treatment most frequent AEs were any on-treatment AEs groups. Most AEs were of Headache, urinary tract similar across the mild-to-moderate intensity. infection, diarrhoea, and treatment groups. Most The most common AEs dizziness. AEs mild-to-moderate were headache, intensity. The most nasopharyngitis, diarrhoea, common AEs were urinary tract infections and headache, falls. nasopharyngitis, diarrhoea, The incidence of drug- dizziness and influenza. related AEs, AEs leading The incidence of drug- to withdrawal, and SAEs related AEs, AEs leading similar across the to withdrawal, and serious treatment groups: 6%– adverse effects (SAEs) 15%; 2%–6%; 2%–7% similar across treatment respectively. Three deaths groups: 7%–13%; 7%–9%; reported (intepirdine 35mg, 8%–12% respectively. 10 donepezil, and placebo, all deaths reported (35mg, n=1). None of the deaths n=4; 15mg, n=5; placebo, considered to be drug n=1). None of the deaths related. considered to be drug Changes in haematology, related. clinical chemistry, Changes in haematology, urinalysis, vital signs, and clinical chemistry, ECG parameters generally urinalysis, vital signs, and small, not clinically ECG parameters generally relevant, and comparable small, not clinically across treatment groups. relevant, and comparable across treatment groups. Expected - - - reporting date

Trial NCT00348192, AZ3106242; intepirdine vs NCT02910102, RVT-101-2003; donepezil vs placebo; phase II. intepirdine vs placebo; phase II. Sponsor GlaxoSmithKline. Axovant Sciences Ltd. Status Published. Ongoing. Source of Publication22, trial registry23, manufacturer. Trial registry24, manufacturer. information Location EU (incl UK), Chile and Russian USA. Federation. Design Randomised, placebo-controlled. Randomised, placebo-controlled.

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Participants n=198; probable mild-to-moderate n=40 (planned); aged 50-89 yrs; a clinical Alzheimer's disease as determined by the diagnosis of Alzheimer’s disease; MMSE NINCDS-ADRDA and DSM-IV criteria with score 14-26; gait impairment; stable an MMSE score of 12-24; no other causes background acetylcholinesterase inhibitor of dementia such as vascular damage, therapy. depression, bipolar affective disorder, schizophrenia, syphilis, vitamin B12 deficiency or thyroid deficiency; no other medication; no conditions which might be exacerbated by exposure to donepezil; no known hypersensitivity to sunlight or seizures. Schedule Randomised to intepirdine 15mg or 35mg Randomised to oral intepirdine 35mg or oral; donepezil 5 or 10mg; or placebo, all placebo; both once daily. once daily.

Follow-up Active treatment for 24 wks, follow-up 24 Active treatment 12 wks, follow-up 12 wks. wks. Primary Cognition and function; ADAS-Cog; Quantitative gait measurements based on outcome/s CIBIC+. computerized gait assessment tools. Secondary Behavioural symptoms; ADL; caregiver AEs. outcome/s burden; safety and tolerability; pharmacokinetic profiling; efficacy related to ApoE and 5-Hydroxytryptamine Receptor 6 (HTR6) status; NPI; DAD; MMSE; cerebral transit time; ACQLI. Key results At week 24: drug-placebo treatment - differences in CIBIC+ score -0.17 for intepirdine and -0.28 for donepezil; drug- placebo treatment differences in ADAS- Cog score -0.4 for intepirdine and -1.2 for donepezil. All treatments were generally safe and well tolerated. Adverse On-treatment AEs reported by 35% of - effects subjects. The most frequent AEs were (AEs) nasopharyngitis, headache, urinary tract infection, upper abdominal pain, and nausea. Expected - Estimated primary completion date reporting September 2017. date

ESTIMATED COST and IMPACT

COST

The cost of intepirdine is not yet known. The cost of other selected treatments specifically licensed for Alzheimer’s disease are listed in the following table.

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Drug Dose Cost for 28 days’ treatment 25 Donepezil (5mg) 5mg once daily for one month then increased to a £1 maximum of 10mg if necessary. Galantamine (8mg) 4mg twice daily for 4 weeks then increased to 8mg twice £25 daily for 4 weeks; maintenance 8-12mg twice daily. Rivastigmine (1.5mg) Initially 1.5mg twice daily, increased in steps of 1.5mg £7 twice daily at intervals of at least 2 weeks. Memantine (10mg) Initially 5mg once daily, increased in steps of 5mg at £2 weekly intervals to a maximum of 20mg daily.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services: expert  Decreased use of existing services opinion suggests that there might be an increased need for monitoring due to the side effect burden of intepirdinec.

 Re-organisation of existing services  Need for new services

 Other  None identified: intepirdine is administered as an oral medication which could be initiated in secondary care with GPs taking over after an initial period or it could be initiated in primary care. Expert opinion suggests that there would be little effect on servicesc.

Impact on Costs and Other Resource Use

 Increased drug treatment costs: expert  Reduced drug treatment costs opinion suggests that there would be little prospect for cost savings based on the benefits seen in phase II studiesc.

 Other increase in costs  Other reduction in costs

 Other  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion suggests that it is likely that any effect of intepirdine would be small as patients would already have an increase in the neurochemical used and the loss of neurones mean there would be a ceiling effect of the treatment. However it should be noted that a small effect on a larger number of people may address the disease burdenc.

c Expert personal communication

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REFERENCES

1 ClinicalTrials.gov. A phase 3, double-blind, randomized Study of RVT-101 versus placebo when added to existing stable donepezil treatment in subjects with mild to moderate Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT02585934 Accessed 07 September 2016. 2 National Institute for Health and Clinical Excellence. Dementia: Supporting people with dementia and their carers in health and social care. Clinical guideline CG42. London: NICE; November 2006. 3 National Institute for Health and Clinical Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. Technology appraisal TA217. London: NICE; March 2011. 4 Alzheimer’s Society. Helping you to assess cognition – A practical toolkit for clinicians. www.alzheimers.org.uk/site/scripts/download_info.php?fileID=2532 Accessed 10 October 2016. 5 Alzheimer’s Association. Tests for Alzheimer’s Disease and Dementia. www.alz.org/alzheimers_disease_steps_to_diagnosis.asp Accessed 10 October 2016. 6 Alzheimer’s Society. Statistics. www.alzheimers.org.uk/statistics Accessed 07 September 2016. 7 NHS Choices. Alzheimer’s disease. www.nhs.uk/conditions/Alzheimers- disease/Pages/Introduction.aspx Accessed 07 September 2016. 8 Luengo-Fernandez R, Leal J and Gray A. Dementia 2010: the economic burden of dementia and associated research funding in the United Kingdom. Alzheimer’s Research Trust, 2010. www.alzheimersresearchuk.org 9 Health & Social Care Information Centre. Hospital episode statistics for England. Admitted patient care, 2014-15. www.hscic.gov.uk 10 Office for National Statistics. Deaths registered in England and Wales (series DR) - 2014. www.ons.gov.uk 11 NHS Clinical Knowledge Summaries. Dementia. August 2016. cks.nice.org.uk/dementia#!topicsummary Accessed 07 September 2016. 12 Hort J, O’Brien JT, Gainotti G et al. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. European Journal of Neurology 2010;17(10):1236-1248. 13 O’Brien JT and Burns A (on behalf of the British Association for Psychopharmacology Dementia Consensus Group). Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. Journal of Psychopharmacology 2011;25(8):997-1019. 14 European Medicines Agency. Guideline on medicinal products for the treatment of Alzheimer’s disease and other dementias. London: EMEA; 2008. 15 Scottish Intercollegiate Guidelines Network. Management of patients with dementia. National clinical guideline 86. Edinburgh: SIGN; February 2006. 16 ClinicalTrials.gov. A long-term, open-label extension study of the safety and tolerability of RVT- 101 in subjects with Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT02586909 Accessed 07 September 2016. 17 Maher-Edwards G, Watson C, Ascher J et al. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2015;1(1):23-36. 18 ClinicalTrials.gov. Study AZ3110866, a fixed dose study of SB-742457 versus placebo when added to existing donepezil treatment in subjects with mild-to-moderate Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT00710684 Accessed 07 September 2016. 19 ClinicalTrials.gov. Study AZ3110865, a study comparing SB-742457 or donepezil versus placebo in subjects with mild-to-moderate Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT00708552 Accessed 07 September 2016. 20 Maher-Edwards G, Zvartau-Hind M, Hunter AJ et al. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Current Alzheimer Research 2010;7(5):374-85. 21 ClinicalTrials.gov. A phase IIa/b double-blind, randomised, placebo-controlled, linear trend design dose-ranging study to investigate the effects of 24 weeks of monotherapy with SB-742457 on cognition in subjects with mild to moderate Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT00224497 Accessed 07 September 2016.

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22 Maher-Edwards G, Dixon R, Hunter J et al. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. International Journal of Geriatric Psychiatry 2011;26(5):536-544. 23 ClinicalTrials.gov. A double-blind, randomised, placebo-controlled, parallel group study to investigate the effects of SB-742457, donepezil and placebo on cognition in subjects with mild to moderate Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT00348192 Accessed 07 September 2016. 24 ClinicalTrials.gov. A phase 2, double-blind, randomized, placebo-controlled crossover study evaluating the effect of RVT-101 on gait and balance in subjects with Alzheimer's disease, dementia with Lewy bodies, or Parkinson's disease dementia. www.clinicaltrials.gov/show/NCT02910102 Accessed 28 September 2016. 25 Joint Formulary Committee. British National Formulary. BNF June 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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