RILUZOLE FOR AMYOTROPHIC LATERAL SCLEROSIS WHAT IS THE

RILUZOLE FOR AMYOTROPHIC LATERAL SCLEROSIS: WHAT IS THE BENEFIT? Case presentation Neurology Rotation Rajwant Minhas April 2012 1

Outline • • • Learning Objectives Case Background: ALS Clinical Question Results Assessment Plan Monitoring Follow up

Learning Objectives • Be able to describe Amyotrophic Lateral Sclerosis in regards to: – Incidence – Pathophysiology – Signs/Symptoms • Discuss management of ALS • Discuss the evidence behind efficacy and safety of Riluzole

Patient Information • GP 73 yo (175 cm, 67 kg) East-Indian Male • Admitted Mar 21, 2011 • C/C: Drowsiness, weakness • HPI: – Had a fall 3 days PTA, slurred speech and unable to walk – Fell 3 wks ago, right sided weakness

Review of Systems • • • CNS: Temp = 37. 7 C HEENT: Dysarthria Resp: – RR = 18, FVC (Sitting) = 16% of predicted, FVC (Supine) = 21% of predicted – Significant diaphragmatic weakness and hypoventilation, orthopnea, dyspnea CVS: – BP = 107/60 mm Hg, HR = 76/min GI/GU/Renal: – SCr = 52, BUN = 4, e. GFR >120 MSK/Skin/Extremities: Weakness, neuropathic pain Date Test Results April 4, 2012 Head MRI Cervical spondylosis but no significant abnormality in cervical spine Mar 30, 2012 EMG Clear motor neuropathy affecting bulbar, thoracic, cervical & lumbar March 21, 2012 Head CT No evidence of acute infarction or hemorrhage

Patient Information PMH MPTA • 4 yr hx of weakness affecting all regions including bulbar, thoracic, cervical & lumbar – New diagnosis of ALS • BPH and urethral stenosis with a previous dilatation of the urethra Tamsulosin 0. 4 mg PO daily • HTN Irbesartan/HCTZ (300 mg/25 mg) PO daily • GERD • Bilateral Knee replacement Lansoprazole 30 mg daily • Mild central spinal stenosis 6

Current Medications HTN Candesartan 8 mg PO daily GERD Pantoprazole 40 mg PO BID BPH Tamsulosin 0. 8 mg PO daily GI Motility Metoclopramide 10 mg PO BID ½ H AC DVT Prophylaxis Dalteparin 5000 Units SC daily Constipation Sennosides 24 mg PO daily Urinary Retention Bethanechol 37. 5 mg PO TID AC Insomnia Zopiclone 3. 75 -7. 5 mg PO HS PRN Heart burn Al/Mg antacid 15 -30 m. L PO Q 4 H PRN Fever/ Muscoskeletal Pain Acetaminophen 325 -650 mg PO Q 4 -6 H PRN Nausea Dimenhydrinate 25 -50 mg PO Q 4 H PRN

Medical Problem List • ALS • Neuropathic Pain

Drug Related Problems • GP is experiencing symptoms of ALS (slurred speech, left side weakness) and would benefit from reassessment of current drug therapy • GP is experiencing neuropathic pain is his feet and would benefit from reassessment of current drug therapy

Amyotrophic Lateral Sclerosis • A rapidly progressive neuromuscular disease • Neuronal death paralysis of voluntary muscles • Exact cause unknown • Assumed glutamate (1° excitatory neuron) plays a key role – Toxic concs. in synaptic cleft result in neuron destruction • Most people die from respiratory failure – Usually within 3 to 5 years from symptom onset – ~ 10% survive for >10 years

Amyotrophic Lateral Sclerosis • • Incidence: ~ 2 per 100, 000 per annum Prevalence: 25, 000 pts in N. America 40 and 60 years of age most affected Men > women 95% sporadic, remaining inherited Affects all ethnic and socio-economic groups Age and family history only established risk factors Canadian Coordinating Office for Health Technology Assessment; 2003. Technology report no 37.

Symptoms of ALS • Weakness in limb and bulbar muscles – Limb onset is most common (~80%) followed by – Bulbar (~20%) and respiratory onset (~1%) Upper motor neuron symptoms Lower motor neuron symptoms Weakness Hyperreflexia Hyporeflexia Spasticity Muscle atrophy Loss of dexterity Fasciculations (GP: tongue, entire chest, thoracic, pectorals, paraspinals) Slowed movements Muscle cramps Hypotonicity or flaccidity

Diagnosis of ALS • No definitive test • Presence of upper and lower motor neuron signs in a single limb is strongly suggestive • Electromyography (EMG) – Detects electrical activity in muscles

Ethical Challenges • Begins with breaking the news to patient – Avoid being personal or dismissive • Physical and emotional stress • Use of life-sustaining therapies: – Long term mechanical ventilation – Feeding tube • Symptomatic management options • Surrogate decision makers

Non-curable disease Is there anything we can use to slow disease progression?

Riluzole Inactivated • Only FDA-approved drug available to treat • Exact MOA unknown • Shown to prolong survival by several months, time to tracheostomy or ventilation support • Does not reverse already done damage Decreases glutamate release

The Controversy Concerns about therapeutic effect persist: • Modest prolongation of survival • Relatively high cost (~ $12, 000/year) • Use in patients who do not fulfill the study entry criteria (age <75, duration <5, Vital capacity >60% of predicted value)? – Use in tracheotomised patients? • Stop at advanced stages of the disease. If so, when?

Clinical Question P: In a 73 year old male diagnosed with ALS with symptoms of 4 years I: Riluzole 50 mg BID C: Placebo O: Slowing down disease progression, prolonging survival and quality of life

Literature Search • Search Terms: – Riluzole, ALS – Limitations: Adults, English • Results: – 1 Cochrane review – 1 Canadian Coordinating Office for Health Technology Assessment (CCOHTA) review – National Institute for Clinical Excellence (NICE) review

Cochrane Review • Objective: – To examine the efficacy of riluzole in: • Prolonging survival • Delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival – Assess the effect of riluzole upon functional health

Cochrane Review • Primary outcomes: 1. Pooled hazard ratio based on % mortality (or tracheostomy) for 100 mg riluzole vs. placebo over all time points • Secondary outcomes: 1. Risk ratios (RRs) based on % mortality at 12, 18 months for 100 mg riluzole vs. placebo 2. RRs based on % mortality as function of time at 12 months: all doses of riluzole vs. placebo 3. Muscle strength assessed by manual muscle testing 4. Functional scales 5. Quality of life of patients and caregivers 6. Adverse effects from riluzole

Bensimon 1994 (Placebo/Riluzole) Lacomblez 1996 Yanagisawa 1997 Bensimon 2002 P 78/77 242/717 97/98 86/82 I Riluzole 100 mg Riluzole 50 mg, 100 mg, 200 mg Riluzole 100 mg daily Riluzole 50 mg BID C Placebo O Survival and changes in functional status after 12 months of tx Tracheostomy-free survival (included death from any cause), tracheostomy, and intubation with artificial ventilation leading to tracheostomy) Disease progression utilizing multiple measures (walking, arm function, tracheostomy, ventilation, tube feeding Time to failure (considered to be death, tracheostomy or intubation with artificial ventilation) More advanced disease

Yanagisawa 1997 • • P: 195 patients in Japan I: Riluzole 100 mg daily C: Placebo O: Disease progression utilizing multiple measures (walking, arm function, tracheostomy, ventilation, tube feeding) • Full data on tracheostomy-free survival not available • Excluded from Cochrane meta-analyses Igakuno Ayumi 1997; 182: 851 -66. 24

Results • 1⁰ outcome measure: pooled HR based on % mortality (or tracheostomy) from 3 trials over all time points • Riluzole 100 mg slight benefit for the homogenous group of patients in the first 2 trials, – P=0. 042, HR 0. 80, CI 0. 64 to 0. 99 – No evidence of heterogenity (P=0. 33) • Median survival: – Riluzole = 15. 5 months – Placebo = 13. 2 months

Results • On addition of Bensimon 2002 trial – Evidence of heterogeneity (P < 0. 0001) • Overall tx effect ↓ but still significant (HR 0. 84, 95% CI 0. 698 -0. 997, P value =0. 046) • 9% gain in the probability of surviving 1 year (49% in the placebo and 58% in the riluzole group), ↑ median survival from 11. 8 to 14. 8 months • ARR with the 100 mg dose @ 12 months = 9%. • NNT to delay 1 death until after 12 months = 11 • Small beneficial effect on both bulbar and limb function, but not on muscle strength

Pooled Survival Time in Months HR from all 3 trials: 16% ↓ in the HR Not quite statistically significant (P=0. 056) A 10% absolute ↑ in the probability of survival for 1 year (56% in placebo group and 66% in the riluzole group) Solid lines: Pooled results from 2 trials that were homogeneous

Results: Safety Study Adverse Effect Combination of 3 trials Nausea, Asthenia Vomiting, diarrhea, anorexia and dizziness somewhat more frequent in Riluzole but did not reach statistical significance ↑ ALT No serious adverse effects from Riluzole in any study

Cochrane Review: Conclusion • Riluzole 100 mg daily prolongs median survival by 2 -3 months in patients with: – Probable and definite ALS with symptoms <5 years, FVC >60%, age < 75 yrs – Reasonably safe – More studies required in older patients and those with more advanced disease

NICE Review: Conclusion • Limited evidence of benefit in tracheostomy-free survival = combined endpoint of time to tracheostomy + death • At best, riluzole postpones death for a few months without precluding the need for supportive care and practical help • Retrieved the tracheostomy-free survival results of Yanagisawa 1997 trial – Overall conclusion similar as Cochrane’s 30

Review • Systematic review • Objective: To assess the potential benefits and harms of riluzole • Outcomes: – All-cause mortality and tracheostomy-free survival – All-cause morbidity – Patient withdrawals due to adverse events – Number of patients experiencing adverse events – Quality of life – Time to tracheostomy • Focuses on all-cause mortality, morbidity (including drugrelated morbidity) or the quality of life.

Canadian Coordinating Office for Health Technology Assessment; 2003. Technology 32 report no 37.

Conclusions • Potential to ↓ serious morbidity in some patients at the cost of causing some drug intolerance (withdrawals due to adverse events) • No information to describe its impact on Qo. L or time to tracheostomy alone. • More adequate reporting of adverse events required Canadian Coordinating Office for Health Technology Assessment; 2003. Technology 33 report no 37.

Limitations of Studies • Small population size • Relatively short duration (12 to 18 months) • No information of quality of life, time to tracheostomy • Generalizability of findings uncertain: 363 of 1477 patients (25%) in RCTs were either older, had more advanced disease or were Japanese • Few North American patients were included

Implications to Practice • More studies required to examine the effect on: – Qo. L – Functionality – In different subgroups (older and more severe patients vs. mild and younger patients) • Survival data: 50 -month survival data but these data unavailable • Ethnicity of our patient – Indians appear to have a relatively younger age of onset, prolonged survival, relatively slow course • (Journal of the Neurological Sciences 272 (2008) 60 -70)

Recommendations • Continue with current regimen of Riluzole

Follow-Up • Depression: Mirtazapine 15 mg PO HS • PEG tube placement: To maintain adequate fluid intake • Respiratory complications: Tracheostomy, Intermittent positive pressure ventilation [IPPV] or bilevel positive airway pressure [BIPAP]) • Neuropathic pain: Gabapentin 100 mg PO TID Amitriptyline 20 mg PO HS • Swallowing status has deteriorated

Monitoring Endpoint Expected Change Frequency CNS depression Improvement Ongoing Neutropenia Absent Once a week LFTs ↑ in transaminases Absent Once a month Nausea Absent Ongoing Asthenia (abnormal physical weakness or lack of energy) No worsening Ongoing Interstitial lung disease (Dyspnea, cough, chest pain) Absent Ongoing

Questions ?