Clinical trials faces 2010


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  • Further studies to see if effect is due to transneural transport may be needed In a study by Hussain, et al in the Biological and Synthetic Membranes, 1989, IN administration in humans of lipophilic propranolol resulted in blood levels similar to those observed following IV administration (60 ng/ml)
  • Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomized study. Setting: Pediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centers but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.
  • Greg: These 3 slides are from the ANTs patients. The first 2 show that focal discharges on the EEG can be seen focally on biopolar recordings from the ANTs electrodes (they are shown at a different gain in referential and bipolar montages. The last slide shows a delay from the right frontal to left frontal regions (across the callosum) to the ANTs: I.e. frontal regions to thalamus in this patient with a right frontal focus with rapid spread. The ANTs stimulator stopped her falls. This slide supports a proposed functional disruption of conduction from the frontal to more central regions, which might be responsible for the therapeutic effect (the stim. Was off the entire time these recordings were obtained).
  • Clinical trials faces 2010

    1. 1. New Therapies and News from Clinical Trials Jacqueline A French MD NYU Epilepsy Center
    2. 2. Current issues to discuss <ul><li>How are we doing with our current treatments? </li></ul><ul><li>Drugs/Devices recently approved </li></ul><ul><li>Drugs/devices in development </li></ul>
    3. 3. Definition of Drug Resistant Epilepsy (International League Against Epilepsy) <ul><li>“ Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.” </li></ul><ul><li>No seizure frequency requirement </li></ul>
    4. 4. How Common is Drug Resistant Epilepsy? Long-Term Follow-Up of Mixed Population (N=525) * *Epilepsy Unit, Glasgow, Scotland 1984-1997 Kwan P, Brodie MJ. N Engl J Med 342:314, 2000 Seizure-free 63% (n=333) Uncontrolled 37% (n=192)
    5. 5. Resistance vs Syndrome Semah F et al. Neurology 51:1256, 1998 45% 35% 82% 27% % of Seizure-Free Patients n 33 337 445 294 Global disturbance Genetic Known Cause Unknown cause Generalized Focal 0 20 40 60 80 100 Difficult to control Easy to control
    6. 6. Seizure Control vs Lesion Location / Etiology Post-stroke Vascular Tumor Normal Head Cortical Isolated Dual malformation MRI trauma dysgenesis hippocampal pathology* sclerosis *HS + another lesion Semah F et al. Neurology 51:1256, 1998 0 20 40 60 80 100 0 20 40 60 80 100 % of Seizure-Free Patients 54% 50% 46% 42% 30% 24% 11% 3% n 26 57 50 268 50 81 224 38 Difficult to control Easy to control
    7. 7. How do new therapies get on the market? <ul><li>Early trials may be done by researchers at Universities </li></ul><ul><li>Most drugs and devices (even if the idea comes from research labs or the National Institutes of Health (NIH) will be tested by companies that eventually will sell the product </li></ul><ul><li>The cost of developing a new drug is $800 million to 2 Billion and takes 12-15 years </li></ul><ul><li>Companies need to partner with clinical researchers and doctors to perform good trials </li></ul>
    8. 8. The course of drug development <ul><li>Pre-Clinical testing </li></ul><ul><ul><li>10,000 250 10 </li></ul></ul><ul><ul><li>(compounds) (get to animal testing) (enter human tests) </li></ul></ul><ul><li>Phase I </li></ul><ul><ul><li>Testing in about 100 normal volunteers </li></ul></ul><ul><ul><li>Developer needs to get approval from FDA in the form of an NDA (new drug application) </li></ul></ul><ul><li>Phase II/III </li></ul><ul><ul><li>Tests to determine if therapy is safe and effective </li></ul></ul>
    9. 9. The course of drug development <ul><li>Phase II/III (continued) </li></ul><ul><ul><li>For a drug, At least 2 trials with a control group (usually placebo) </li></ul></ul><ul><ul><ul><li>Drug must be better than “placebo” (how much?) </li></ul></ul></ul><ul><ul><ul><li>Can see how frequent dose-related side effects are compared to placebo </li></ul></ul></ul><ul><ul><li>For a device a single trial may be sufficient </li></ul></ul><ul><ul><li>Overall, 1500-3000 pts exposed to drug, to look for “rare” side effects </li></ul></ul>
    10. 10. SINCE 1998 2000 0 5 10 20 Zonisamide Felbamate Gabapentin Topiramate Oxcarbazepine Tiagabine Levetiracetam Pregabalin Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine 1990 2010 Lacosamide Rufinamide
    11. 11. DO WE NEED MORE NEW THERAPIES? <ul><li>Problem with current AEDs: </li></ul><ul><ul><li>Seizure control </li></ul></ul><ul><ul><ul><li>Still 40% with therapy resistance </li></ul></ul></ul><ul><ul><ul><li>New AEDs over last 20 years have not changed this equation! </li></ul></ul></ul><ul><ul><li>Safety/tolerability </li></ul></ul><ul><ul><ul><li>Some new (and old) AEDs still have important safety and tolerability problems </li></ul></ul></ul>
    12. 12. Recent Drug approvals <ul><li>Drugs </li></ul><ul><li>Vimpat (Lacosamide): Approved October 2008 </li></ul><ul><ul><li>Approved for partial-onset (focal) seizures </li></ul></ul><ul><li>Banzel (rufinamide) Approved November 2008 </li></ul><ul><ul><li>Approved for Lennox-Gastaut Syndrome (a form of severe epilepsy, often associated with intellectual impairment) </li></ul></ul>
    13. 13. Recent Drug approvals <ul><li>Sabril (Vigabatrin): August 2009 </li></ul><ul><ul><li>Available in Europe for over a decade </li></ul></ul><ul><ul><li>Known to cause permanent vision problems (seeing to the sides) in 30% of people </li></ul></ul><ul><ul><li>Approved for infantile spasms and treatment-resistant partial onset (focal) seizures </li></ul></ul>
    14. 14. Drugs in late stages of Development <ul><li>Brivaracetam (Rikelta) </li></ul><ul><li>Eslicarbazepine (Stedesa) </li></ul><ul><li>Retigabine (Ezogabine) </li></ul>
    15. 15. BRIVARACETAM (Rikelta) <ul><li>Similar mechanism to Levetiracetam (Keppra TM ) but much stronger in animal models </li></ul><ul><li>Also has sodium channel blocking activity </li></ul><ul><li>Should work in many seizure types </li></ul><ul><li>Trials underway at NYU and elsewhere </li></ul>
    16. 16. Responder Rates <ul><li>SEIZURE-FREEDOM RATES </li></ul>50% SZ REDUCTION RATES Results from logistic regression (50% responder rate); ITT population ITT population: n=208; 110M, 98F; age range 16–65 y; p -value versus PBO PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 20 30 40 50 60 16.7 p = 0.047 32.0 p = 0.002 44.2 p = 0.001 55.8 % Responders PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 60 % Patients 1.9 1/54 8.0 4/50 7.7 4/52 7.7 4/52 10 20 30 40 50
    17. 17. Brivaracetam Adverse Events PBO BRV5 BRV20 BRV50 Patients (N) 54 50 52 52 Permanent study drug discontinuation 2 (3.7) 3 (6.0) 1 (1.9) 0 Patients with ≥1 AE, n (%) 29 (53.7) 26 (52.0) 29 (55.8) 28 (53.8) Total AEs 59 50 72 56 AEs reported in ≥ 5% patients Headache Somnolence Influenza Dizziness Neutropenia Fatigue 4 (7.4) 4 (7.4) 4 (7.4) 3 (5.6) 1 (1.9) 2 (3.7) 4 (8.0) 1 (2.0) 4 (8.0) 1 (2.0) 4 (8.0) 0 2 (3.8) 3 (5.8) 0 0 2 (3.8) 2 (3.8) 1 (1.9) 3 (5.8) 1 (1.9) 4 (7.7) 0 3 (5.8)
    18. 18. Eslicarbazepine (Stedesa) <ul><li>A “third generation” Carbamazepine (Tegretol TM ) </li></ul><ul><li>Improves on second generation (Trileptal TM ) </li></ul><ul><ul><li>Less effect on blood tests (sodium) </li></ul></ul><ul><ul><li>Smoother release may produce less side effects </li></ul></ul><ul><li>Hopefully will work equally as well </li></ul><ul><li>Trials underway at NYU and elsewhere </li></ul>
    19. 19. Double-Blind Placebo-Controlled Add-on Trial of Eslicarbazerpine (ESL) in Refractory Partial Epilepsy: 50% Responder Rates (n=143) 28% 41% % Patients 54%* Placebo ESL ESL 1200 mg/d 1200 mg/d o.i.d b.i.d. (* P=0.008 vs PL) Bialer et al., Epilepsy Res 2007;73:1-52.
    20. 20. Retigabine <ul><li>Works on a NEW channel that other drugs don’t work on (Potassium channel) </li></ul><ul><li>Defect in potassium channel linked to one inherited form of epilepsy (benign neonatal seizures) </li></ul><ul><li>Trials completed, submitted to FDA for approval </li></ul>
    21. 21. Patients with > 50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance) Intent-to-treat Study 302 Study 301 *p<0.005 **p<0.001 % Patients 179 181 178 152 153 Placebo 600 900 Placebo 1200 RTG RTG
    22. 22. Most Common Adverse Events ( > 10% Incidence) % Patients Placebo (N=331) RTG 600 (N=181) RTG 900 (N=178) RTG 1200 (N=153) Dizziness 10 17 26 40 Somnolence 13 14 26 31 Fatigue 5 17 15 16 Confusion 1 2 5 14 Dysarthria 1 5 2 12 Headache 16 11 17 12 Ataxia / gait disturbance 2 3 5 12 Urinary tract infection 5 1 2 12 Tremor 3 2 9 11 Vision blurred 2 <1 5 11 Nausea 5 6 7 10
    23. 23. Discontinuations Due to Adverse Events *Dose-related <ul><li>Adverse event as primary reason for discontinuation </li></ul><ul><ul><li>Placebo (N=331) </li></ul></ul>600 (N=181) 900 (N=178) 1200 (N=153) <ul><ul><li>8% </li></ul></ul>14% 26% 27% <ul><li>Cause for discontinuation in >3% of patients </li></ul><ul><ul><li>Dizziness* </li></ul></ul><ul><ul><li>Confusion* </li></ul></ul><ul><ul><li>Somnolence </li></ul></ul><ul><ul><li>Fatigue </li></ul></ul>
    24. 24. Current pharmacologic therapy in epilepsy <ul><ul><li>Preventive (antiepileptic medications): </li></ul></ul><ul><ul><ul><li>Standard for nearly all patients </li></ul></ul></ul><ul><ul><ul><li>Not effective for an “acute” seizure </li></ul></ul></ul><ul><ul><li>Abortive or rescue medications </li></ul></ul><ul><ul><ul><li>Seizures in clusters </li></ul></ul></ul><ul><ul><ul><li>Prolonged seizures </li></ul></ul></ul><ul><ul><ul><li>One seizure after another (status epilepticus) </li></ul></ul></ul>
    25. 25. Options for abortive therapy <ul><li>Current: </li></ul><ul><ul><li>Rectal Diazepam (valium) </li></ul></ul><ul><ul><ul><li>Mostly used in children </li></ul></ul></ul><ul><ul><ul><li>Often not feasible, or may be a delay in administration </li></ul></ul></ul><ul><ul><li>Buccal or nasal preparations </li></ul></ul><ul><ul><ul><li>Not FDA approved </li></ul></ul></ul><ul><li>Future </li></ul><ul><ul><li>Intranasal Midazolam </li></ul></ul><ul><ul><ul><li>Studies beginning soon at NYU </li></ul></ul></ul>
    26. 26. Advantages of Nasal Drug Delivery <ul><li>Easy access with/without patient cooperation </li></ul><ul><li>Rapid and extensive absorption through the nasal mucosa </li></ul><ul><li>Convenient and easy administration </li></ul><ul><li>Needle-less </li></ul>
    27. 27. Comparative Efficacy of IN MDZ vs IV DZP Lahat E, et al. BMJ . 2000;321:83-86. Dose = 0.3 mg/kg Dose = 0.2 mg/kg N=47 children with febrile seizures (>10 min) 3.5 min 5 min 6.1 min 8 min Main outcome measures: Time from arrival at hospital to drug administration & time to seizure cessation Observation period = 60 minutes
    28. 28. Who can be in a clinical trial of a new therapy? <ul><li>People on 2-3 stable antiepileptic drugs, still experiencing more than one seizure/month (often requires 3-4) </li></ul><ul><li>Able to keep seizure counts </li></ul><ul><li>Usually over 18, unless trial is specifically for children </li></ul><ul><li>Not planning pregnancy </li></ul>
    29. 29. What should I ask my doctor about a new drug? <ul><li>How many patients have been exposed to date? </li></ul><ul><li>What are the common dose-related side effects </li></ul><ul><li>Were there any irreversible side effects, or will the problems go away when I lower the dose? </li></ul><ul><li>Was this drug studied for my seizure type? </li></ul><ul><li>How well did the drug do compared to placebo? </li></ul>
    30. 30. Devices under study Medtronic, “Sante” Trial NeuroPace “RNS” Trial
    31. 31. <ul><li>Electrodes surgically placed in the thalamus, a deep part of the brain, on both sides </li></ul><ul><li>Stimulation every 5 minutes </li></ul><ul><li>Strength and duration of stimulation can be adjusted </li></ul><ul><li>Like Vagus nerve stimulator, patient can “trigger” stimulation for an aura or seizure </li></ul>Medtronic SANTE Trial Stimulation of Anterior Thalamus for Epilepsy
    32. 32. Stimulating Electrode, 4 contacts Electrode (4 contacts )
    33. 33. Results of stimulation (sham)
    34. 34. Deep Brain Stimulation Study <ul><li>Treatment worked better for people with epilepsy from the temporal lobe, and did not work as well in those with frontal, parietal and occipital epilepsy. </li></ul><ul><li>Treatment worked just as well after surgery and VNS. </li></ul><ul><li>The infection rate was 10.9 % and the rate of asymptomatic intracranial hemorrhage was 1.3 % per lead implant. </li></ul><ul><li>There was a significantly higher incidence of spontaneously self-reported depression, memory impairment, and anxiety in the active group compared to the control group during the blinded phase, </li></ul>
    35. 35. Seizure frequency changes 2 years after randomization
    36. 36. Radiosurgery <ul><li>“ Gamma Knife” </li></ul><ul><li>Alternative to open </li></ul><ul><li>surgery </li></ul><ul><li>Using a special helmet, </li></ul><ul><li>radiation is focused on a </li></ul><ul><li>single spot in the brain-the spot where seizures arise, destroying the focus, while passing harmlessly through normal tissue. Less invasive than standard surgery </li></ul><ul><li>So far produces seizure freedom about 2/3 of the time, about the same as open surgery. </li></ul>
    37. 37. Gamma Knife <ul><li>Advantages </li></ul><ul><ul><li>Less invasive </li></ul></ul><ul><ul><li>Recovery usually faster </li></ul></ul><ul><ul><li>May cause less harm to normal surrounding tissue, leading to fewer neuropsychological problems in the longterm </li></ul></ul><ul><li>Disadvantages </li></ul><ul><ul><li>Takes a while to work (up to a year), and seizures may get worse before they improve </li></ul></ul><ul><ul><li>Swelling may cause nausea, headache, psychiatric problems </li></ul></ul><ul><ul><li>2/3 need anti-swelling meds (steroids) temporarily </li></ul></ul>
    38. 40. Temporal lobectomy
    39. 41. What happens now? <ul><li>Randomized trial of Gamma knife vs temporal lobectomy </li></ul><ul><li>Could be a good alternative in some patients who do not want to have open surgery </li></ul>
    40. 42. Responsive Neurostimulator <ul><li>Designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms. </li></ul><ul><li>Electrodes are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start). </li></ul><ul><li>Designed to continuously monitor brain electrical activity from the electrodes and, after identifying the &quot;signature&quot; of a seizure's onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure. </li></ul>
    41. 43. RNS with Leads
    42. 44. RNS
    43. 45. Anthony Murro, M.D. Medical College of Georgia
    44. 46. RNS Clinical trial <ul><li>171 patients implanted-half got “sham” stimulation, the other half got true stimulation </li></ul><ul><li>During the last 2 months, mean 29 % percent decrease vs 14 % decrease in the sham stimulation group. </li></ul><ul><li>In the long term (last 12 weeks of treatment): 47 % of subjects experienced a ≥ 50 % decrease in seizure frequency, as compared to their baseline. </li></ul><ul><li>Few adverse events </li></ul>
    45. 47. What happens now? <ul><li>FDA expert panel voted to approve Deep Brain Stimulator (Medtronics) in March 2010 </li></ul><ul><ul><li>Should be on market shortly </li></ul></ul><ul><li>Responsive Neurostimulator (Neuropace) will be evaluated for approval by FDA </li></ul>
    46. 48. Other drugs/devices on the way <ul><li>Drugs: </li></ul><ul><ul><li>Ganaxalone </li></ul></ul><ul><ul><li>ICA-105665 </li></ul></ul><ul><ul><li>Perampanel (E2007) </li></ul></ul><ul><ul><li>T2000: (non-sedating barbiturate) </li></ul></ul><ul><ul><li>YKP3089 </li></ul></ul><ul><ul><li>Huperzine </li></ul></ul><ul><ul><li>NPY gene transfer </li></ul></ul><ul><li>Devices </li></ul><ul><ul><li>Drug Delivery Pumps </li></ul></ul><ul><ul><li>Seizure detection/prevention </li></ul></ul>
    47. 49. Conclusion <ul><li>Without volunteers for clinical trials, no new drugs or devices will be possible </li></ul><ul><li>Many new options are on the way, providing hope for all people with uncontrolled seizures </li></ul>
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