The MNSI

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Presented by Eva Feldman, M.D. at the Anesthetic
and Life Support Drugs Advisory Committee
Meeting on May 16, 2002
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(No Transcript)
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Diabetic Neuropathy

• WHO Definition
• A disease characterized as a progressive loss of
  nerve fibers leading to sensation loss, foot
  ulceration, and amputation

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Myelinated Neuron
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PNS Anatomy
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Diabetic Peripheral Nerve Damage
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Neuropathic Symptoms and Signs

• Symptoms and signs will reflect the type of fiber
  damage
• DPN is primarily a sensory neuropathy
• Thinly myelinated or unmyelinated fibers pain,
  altered cold, heat, light touch
• Large myelinated fibers vibration,
  proprioception
• Most frequently both fiber types are involved

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PNS Anatomy
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Neuropathic Symptoms

• Onset (acute or insidious) and course (monophasic
  or fluctuating)
• Sensory Symptoms Numbness, loss of sensation
  (Negative symptoms, 80 pts) Tingling,
  prickling, burning, pain (Positive symptoms, 20
  pts)
• Motor Symptoms (Rare) Weakness, primarily distal

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Neuropathic Signs

• Inspection Dry, atrophic skin, loss of hair and
  sweating, distal muscle atrophy
• Sensory (most common)
• Vibration and proprioception (large fiber)
• Light touch and pinprick (small fiber)
• Motor (less common) Distal muscle weakness
• Reflexes Absent or depressed

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Diabetic Peripheral Neuropathy
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San Antonio Consensus Statement

• Neurological Disability Score (NDS)
• Quantitative Sensory Testing (VT)
• Autonomic Function Testing (AF)
• Nerve Conductions (NC)
• Without Symptoms (Stage 1 A-C)
• With Symptoms (Stage 2 A-C)

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DCCT Design

• DPN Clinical exam and NCS
• Clinical exam (sensation, reflexes) and symptom
  score 2/3 for probable, 3/3 for definite
  neuropathy
• NCS performed on 1243 patients at baseline and 5
  yr later
• Peroneal MNCV 3.5 m/sec faster in intensive vs
  conventional treatment

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DCCT Neurological Outcome
Adapted from DCCT Research Group. New Engl J Med
1993 329977-986
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MNSI Examination Predicts DCCT Treatment
Assignment in EDIC Year 01 through 04 for Primary
and Secondary DCCT Cohorts
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Aldose Reductase and Alcar Trials

• Tolerstat Primary nerve morphometry and
  sorbitol content Secondary NCV, clinical exam
  (12 mo analysis no sural effect) some effect on
  MNCV
• Zopolrestat (FK-366) Phase III primary endpoints
  as Tolerstat, ½ dose of II, 18 mo interim
  analysis-no effect
• Alcar Primary Nerve morphometry and NCSno
  effect

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Sural Nerve Biopsies in Man
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Axon Counts in Human Sural Nerves
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Axon Loss inDiabetic Neuropathy
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Aldose Reductase Zenerstat

• Entry criteria (2/3) symptoms, signs, abnormal
  NCV in 2 nerves or abn VPT however both surals
  and VPT must be recordable
• Phase II, 52 weeks, DBPC
• Neurology 53580-591, 1999

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Change in NCS Sural and Composite with Zenarestat
Greene DA, Arezzo JC, Brown MB. Neurology
199953580-591
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Change in Nerve fiber Density with Zenarestat
Greene DA, Arezzo JC, Brown MB. Neurology
199953580-591
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Zenarestat Increases the MNFD for Small
Myelinated Fibers
Greene DA, Arezzo JC, Brown MB. Neurology
199953580-591
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Aldose Reductase ZenerstatPhase III Trial

• Entry criteria same as Phase II
• Primary Composite ranked score for median
  forearm sensory, peroneal motor and sural sensory
  CV plus composite ranked score of QST for
  vibratory and cool perception
• Secondary individual NCV, F waves, sural and
  median amplitudes MDNS Health-Related QOL
  (Symptoms, Health Survey
• Discontinued due to renal toxicity

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Nerve Growth Factor

• Randomized double-blind placebo controlled trial
• 250 patients
• Symptomatic diabetic polyneuropathy with
  abnormalities of NCS and QST
• Age range 18-60 years
• NGF given SQ three times per week for 6 months
• Small improvement in sensory symptoms and QST

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Neuropathy Impairment Score (NIS)
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Change in the Lower Limb NIS With NGF
Apfel SC and the NGF Study Group. Neurology
199851695-702
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Changes in CDT and HPT in the hNGF-Diabetic
Neuropathy Study
Apfel SC and the NGF Study Group. Neurology
199851695-702
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Nerve Growth FactorPhase III

• 1019 patients (504 NGF, 515 placebo)
• Primary Change in NIS-LL (17-24,28,29, 34-37 in
  NIS)
• Secondary QST, Neuropathy Symptom and Change
  Questionnaire, NCV, filament
• Unsuccessful

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Measures in Current and Proposed Trials

• NIS-LL plus 2-10 additional tests
• NIS-LL plus 7 VPT, RR with deep breathing, 5
  NCV (peroneal CMAP, MNCV, MNDL), tibial nerve
  (MNDL) and sural (SNAP)
• Rochester Diabetic Cohort .35 change no DPN, .85
  change with DPN yearly NI-LL plus 7 correlates
  with other microvascular complications
• Protocol in Nathan I, II trials (lipoic acid)
• Diabetes Care 221479-1486, 1999
• Neurology 49229-239

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Measures in Current and Proposed Trials

• NIS-LL most frequently abnormalities reflexes
  and vibratory sensation, essentially no motor
  abnormalities
• Corraborated by Fedele et al in gt2300 DPN
  patients
• MNCV of LL and sural SNAP most frequent abnormal
  NCV
• VPTgtCPT
• Question whether RR variability is a viable
  clinical endpoint

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Clinical Endpoints

• Propose a composite score
• NIS-LL (minus questions 17-22 or 17-24)
• Composite NCV
• Quantative Sensory Testing (VPT, CP)
• Secondary endpoints Symptom questionnaire, QOL
• Our experience over the last 12 years clearly
  shows that drug efficacy in DPN can not be judged
  by a single parameter but requires a composite
  score

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Entry Criteria

• Need patients with mild disease so you can
  monitor a change over time
• Aim halt progression, unlikely to show
  improvement
• Requires longer time frame
• Using NIS (2 points), RDNS 3.4 years to show
  decreased progression
• Neurology 49 229-239, 1997