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SYMPTOM MANAGEMENT: PHARMACOLOGIC THERAPY Christopher T. Bever, Jr., M.D. Director, MS CoE - East

SYMPTOM MANAGEMENT: PHARMACOLOGIC THERAPY Christopher T. Bever, Jr., M.D. Director, MS CoE - East June 5, 2004. Progressive. Preclinical. Relapsing. Symptoms in Progressive MS. Time. Hartung HP et al. The Lancet. 2002;360:2018-2025. Symptoms of MS. Ataxia and tremor

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SYMPTOM MANAGEMENT: PHARMACOLOGIC THERAPY Christopher T. Bever, Jr., M.D. Director, MS CoE - East

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  1. SYMPTOM MANAGEMENT: PHARMACOLOGIC THERAPY Christopher T. Bever, Jr., M.D. Director, MS CoE - East June 5, 2004 CMSC, June 2004

  2. Progressive Preclinical Relapsing Symptoms in Progressive MS Time Hartung HP et al. The Lancet. 2002;360:2018-2025. CMSC, June 2004

  3. Symptoms of MS • Ataxia and tremor • Bladder and bowel dysfunction • Cognitive Impairment • Depression • Fatigue • Pain • Sexual dysfunction • Spasticity and weakness • Visual disturbances IOM Report, 2001 CMSC, June 2004

  4. Symptom Classifications • Primary vs. secondary vs. tertiary • Neurological vs. non-neurological • Negative vs. positive • Fixed vs. paroxysmal A. Miller, 2000 CMSC, June 2004

  5. Treatable Symptoms of MS • Ataxia and tremor • Bladder and bowel dysfunction • Cognitive impairment • Depression • Fatigue • Paroxysmal symptoms • Sexual dysfunction • Spasticity • Weakness CMSC, June 2004

  6. Treatable Symptoms of MS • Ataxia and tremor • Bladder and bowel dysfunction • Cognitive impairment • Depression • Fatigue • Paroxysmal symptoms • Sexual dysfunction • Spasticity • Weakness CMSC, June 2004

  7. Treatable Symptoms of MS • Ataxia and tremor • Bladder and bowel dysfunction • Cognitive impairment • Depression • Fatigue • Paroxysmal symptoms • Sexual dysfunction • Spasticity • Weakness CMSC, June 2004

  8. Fatigue in MS • Subjective lack of physical or mental energy to carry out usual activities • Present at some time in 75%-90% of patients with MS • Present daily in 46%-66% CMSC, June 2004

  9. Fatigue: Proposed Treatments • Amantadine • Pemoline • SSRI’s • Amphetamines • Aminopyridines • Modafanil • Behavior modification CMSC, June 2004

  10. Amantadine • Developed as an anti-viral agent • Identified by a chance observation as improving MS fatigue • Class I evidence from four trials supports its use in MS patients • Response rates of 20% to 40% at 100 mg bid CMSC, June 2004

  11. Modafanil • Novel wakefulness-promoting agent • Mechanism of action unknown • Low abuse potential (Schedule IV) • FDA approval for narcolepsy CMSC, June 2004

  12. Phase II Trial in MS • Randomized, patient-blind, placebo-controlled crossover design phase II trial • 72 patients enrolled at two sites • Outcome measures: • FSS (primary) • MFIS • VAS-F • Epworth sleepiness scale CMSC, June 2004

  13. Results: FSS * *p<0.001, Placebo run in vs Modafanil 200mg CMSC, June 2004

  14. Results: MFIS * *p<0.001, Placebo run in vs Modafanil 200mg CMSC, June 2004

  15. Results: VAS-F * *p<0.003, Placebo run in vs Modafanil 200mg CMSC, June 2004

  16. Adverse Events • < 10% of patients • More common during treatment: • Nausea • Anxiety, nervousness • Dry mouth • Insomnia • Diarrhea • Asthenia CMSC, June 2004

  17. Conclusions • Fatigue is one of the most common symptoms in MS patients • Pharmacological treatments are an important part of fatigue management • Amantadine is effective, cheap and well tolerated • Modafanil is effective and well tolerated CMSC, June 2004

  18. Treatable Symptoms of MS • Ataxia and tremor • Bladder and bowel dysfunction • Cognitive impairment • Depression • Fatigue • Paroxysmal symptoms • Sexual dysfunction • Spasticity • Weakness CMSC, June 2004

  19. Weakness • One of the most common and disabling symptoms in MS • Usually due to upper motor neuron dysfunction • Loss of voluntary control exacerbated by de-conditioning • Primary therapy is exercise CMSC, June 2004

  20. Aminopyridine Potassium Channel Blockers • Nonspecific blockers of voltage sensitive potassium channels • Improve action potential propagation in demyelinated axons • Increase transmitter release at synaptic endings CMSC, June 2004

  21. 3,4 Diaminopyridine • Orally active • Short serum half-life • Crosses blood brain barrier poorly • Available for the treatment of Lambert-Eaton Myasthenic Syndrome CMSC, June 2004

  22. Phase II Trial of DAP in MS • Double-blind, placebo-controlled, crossover trial • 22 MS patients with leg weakness • One month treatment periods with up to 100 mg per day • Outcome measures: • Patient and physician impressions of change • Manual motor testing • Quantitative motor testing • Ambulation index CMSC, June 2004

  23. Results: # Improved OutcomeDAPPlacebop Physician IC 21 1 0.005 Patient IC 14 2 0.008 MMT 16 3 0.002 QMT-HS 16 9 0.001 QMT-Q 15 8 0.04 AI 5 0 0.02 CMSC, June 2004

  24. Results: Mean scores OutcomeDAPPlacebop MMT 41.6 39.9 0.002 QMT -HS 130 123 0.001 QMT-Q 231 206 0.04 CMSC, June 2004

  25. Results: Mean Strength Scores CMSC, June 2004

  26. Results: Mean AI Scores CMSC, June 2004

  27. Conclusions • 3,4 DAP treatment can improve leg strength in selected patients • 3,4 DAP treatment can improve ambulation times in a subset of patients • 3,4 DAP treatment causes paresthesias and gastrointestinal adverse events that limit its use • Rarely 3,4 DAP treatment can cause seizures CMSC, June 2004

  28. 4-Aminopyridine • Orally active • Crosses blood brain barrier readily • Longer half-life than DAP • Used to reverse neuromuscular blockade after surgery CMSC, June 2004

  29. Trials of 4-Aminopyridine in MS • Jones et al: Open label pilot • Davis & Stefoski: Controlled crossover • Van Diemen, et al: Randomized, controlled, crossover • Bever et al: Randomized, controlled, crossover • Schwid et al: Randomized, controlled, crossover • Goodman et al: Randomized, DB, PC parallel group CMSC, June 2004

  30. Objectives • Primary: Determine safety of multiple doses of fampridine-SR (one week each of 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day and 80 mg/day). • Secondary: Obtain evidence of efficacy and dose-response using several outcome measures • Standard MS measurements, including timed walk, lower extremity muscle strength, PASAT, 9-hole peg test • Daily Fatigue Diary – Brief Fatigue Inventory Goodman, A, 2002 CMSC, June 2004

  31. CMSC, June 2004

  32. Dose Response- 25 ft Walk CMSC, June 2004

  33. Leg strength Worse Better Fampridine-SR (20-50 mg/day) Placebo CMSC, June 2004

  34. Fampridine-SR (N=25) Placebo (N=11) No. with AEs All AEs 25 (100%) 10 (90.9%) Most Frequently Reported AEs Dizziness 9 (36.0%) 2 (19.2%) Insomnia 9 (36.0%) 1 (9.1%) Paresthesia 8 (32.0%) 1 (9.1%) Nausea 7 (28.0%) 1 (9.1%) Asthenia 7 (28.0%) 1 (9.1%) Headache 6 (24.0%) 1 (9.1%) Tremor 6 (24.0%) 0 Pain 5 (20.0%) 0 Back Pain 5 (20.0%) 0 Anxiety 3 (12.0%) 0 Hypertonia 1 (4.0%) 3 (27.3%) Treatment emergent adverse events CMSC, June 2004

  35. Safety Summary • The most common adverse events in the fampridine treated group were consistent with the findings of previous studies • Dizziness, Insomnia, Parasthesia, Nausea, Asthenia, Headache, Tremor • At doses above 40 mg/day, more severe adverse events were reported, including two cases of seizure (at 60 and 70 mg/day) • As anticipated, the risk of seizure requires further study and characterization particularly in the anticipated dose range CMSC, June 2004

  36. Summary • Safety profile consistent with previous experience • Significant* benefit on timed walking (p=0.04) • Significant* benefit on lower extremity strength (p=0.01) • Evidence of dose-response in 20-40 mg/day range • No evidence of benefit on overall fatigue • Little added benefit, and increased AEs at doses above 50 mg/day *repeated measure ANOVA (weeks 1-7) CMSC, June 2004

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