1 / 36

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

seth-hughes
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related