# Presentation: 376437

## Presented by 

- Eva Feldman, M.D.
- at the
- Anesthetic and Life Support Drugs
- Advisory Committee Meeting
- on May 16, 2002

## Slide 2

## Diabetic Neuropathy

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

## Myelinated Neuron

## PNS Anatomy

## Diabetic Peripheral Nerve Damage

## 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

## PNS Anatomy

## 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

## 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

##  Diabetic Peripheral Neuropathy

## 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)

## 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

## DCCT Neurological Outcome

- Adapted from DCCT Research Group. New Engl J Med 1993; 329:977-986

## MNSI Examination Predicts DCCT Treatment Assignment in EDIC Year 01 through 04 for Primary and Secondary DCCT Cohorts

## 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, 1⁄2 dose of II, 18 mo interim analysis-no effect
- Alcar: Primary: Nerve morphometry and NCS—no effect

## Sural Nerve Biopsies in Man

## Axon Counts in Human Sural Nerves

## Axon Loss inDiabetic Neuropathy

## 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 53:580-591, 1999

## Change in NCS: Sural and Composite with Zenarestat

- Greene DA,  Arezzo JC, Brown MB.  Neurology 1999;53:580-591

## Change in Nerve fiber Density with Zenarestat

- Greene DA,  Arezzo JC, Brown MB.  Neurology 1999;53:580-591

## Zenarestat Increases the MNFD for Small Myelinated Fibers

- Greene DA,  Arezzo JC, Brown MB.  Neurology 1999;53:580-591

## Aldose Reductase:  ZenerstatPhase 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

## 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

## Neuropathy Impairment Score (NIS)

## Change in the Lower Limb NIS With NGF

- Apfel SC and the NGF Study Group.  Neurology 1998;51:695-702

## Changes in CDT and HPT in the hNGF-Diabetic Neuropathy Study

- Apfel SC and the NGF Study Group.  Neurology 1998;51:695-702

## Nerve Growth FactorPhase III  

- 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

## 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 22:1479-1486, 1999
- Neurology 49:229-239

## 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 >2300 DPN patients
- MNCV of LL and sural SNAP most frequent abnormal NCV
- VPT>CPT
- Question whether RR variability is a viable clinical endpoint

## 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

## 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