Clinical trial NCT03942848: Intrathecal Ziconotide Antalgic Efficacy for Severe Refractory Neuropathic
Official title: Assessment of Intrathecal Ziconotide Antalgic Efficacy for Severe Refractory Neuropathic Pain Due to Spinal Cord Lesions.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Severe Refractory Neuropathic Pain
Spinal Cord Lesions
Keywords: Spinal cord lesion
intrathecal infusion
refractory neuropathic pain
ziconotide
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2019-05-08
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Spinal cord injury (SCI) has an average prevalence of 50 per 100.000 in general population (30.000 patients with SCI in France) with estimates of the overall prevalence for severe neuropathic pain ranges from 30 to 51% (up to 10.000 patients in France).

Patients with such spinal lesions may develop neuropathic pain called sublesional pain as perceived in an area below the level of injury. A second type of pain is at level of injury, i.e. perceived in a segmental pattern within the dermatome corresponding the spinal cord and nerve roots. These two types of pain are very harmful and are notoriously difficult to treat probably because of complex pathogenic mechanisms due to abnormal functioning of deafferented spinal and supraspinal nociceptive neurons.

Opioids, whatever be the route of administration, had demonstrated their inefficacy for these patients as well as several surgical techniques. So, chronic pain in relation with spinal lesion can be defined as real refractory pain.

Synaptic release of neurotransmitters is dependent on calcium intake trough voltage dependent channels. Type 2.1 or N-Type channels are specific for nociceptive system and can be blocked by a peptic neurotoxin: Ziconotide. Blocking these specific calcium channels neuromodulates nociception. Intrathecal use of Ziconotide, bringing the active molecule close to its receptors, has a proven clinical impact for a wide variety of pain (4). The intrathecal Ziconotide (ITZ) infusion using an implanted pump is validated for treatment of pain refractory to systemic analgesics (HAS, avis du 14-27 mai 2008). Meanwhile, no data are available in literature on positive effects of ITZ on specific spinal neuropathic pain.

A pilot study was performed by the coordinator team using ITZ on 12 patients with spinal pain: 8 patients had \> 40% decrease of pain on numeric scale, 6 patients beneficiated from implanted pump allowing chronic ITZ treatment inducing 60% numeric scale decrease in average with 1 year follow-up.

Therefore intrathecal Ziconotide could be an excellent candidate for the treatment of spinal pain where the pain generators may be difficult to target by other available treatments.

This study is the first to assess ITZ (as IT antalgic monotherapy) versus placebo with a randomized controlled study with long follow-up. Trials have already been performed but not specially targeted spinal pain, and did not exceed three weeks follow-up.

Long term effects of Ziconotide on memory, cognition and mood have not been evaluated. In fact even though short term adverse effects on higher level functions have been described they have not been assessed in a placebo controlled situation.

Moreover, treating (successfully or not) patients with spinal pain could bring valuable insights both into the mechanisms of pain production in SCI patients and in the mechanisms of Ziconotide action: a positive result on pain below the injury level would imply action on the second or third order synapses of the nociceptive pathways. Similarly an effect at the level of pain, in absence of an effect below the level pain would argue discussion against such action. The impact of ITZ on the different clinical components of pain experienced by the patients, could also give some data on neuromodulation mechanism induced by the therapy.


Eligibility criteria: Inclusion Criteria:

* • Patient \> 18 year old

  * Patients with stabilized spinal cord lesion
  * Patients with refractory neuropathic pain with "Douleur Neuropathique" (DN4) score \>4 at selection and failure at least of 2 classes of antineuropathic pain drugs alone or in association
  * Experiences pain \> 5/10 on numeric scale
  * Patients with a positive trial test to Ziconotide either by lumbar puncture or by continuous infusion above the lesioned level via an implanted catheter
  * Evaluation performed both by a multidisciplinary team in a pain center and a rehabilitation center
  * Patients eligible to surgical implantation of a subcutaneous pump
  * Signed informed consent
  * Patients benefiting from a social insurance system or a similar system

Exclusion Criteria:

* • Life expectancy \< 5 years

  * Suffering from other neuropathic pain or chronic pain due to cancer
  * Being treated with spinal cord stimulation, nerve stimulation, intrathecal analgesic delivery system with analgesic drug (except Baclofen) until the last 6 months
  * Implant ITZ surgery contraindication (MRI or anesthesia contraindication, coagulation disorder, Immunodepression, current infection, critical respiratory and/or heart illness)
  * Unable to operate the ITZ equipment or comply with study requirements
  * Suspicion of substance abuse
  * Current or planned pregnancy
  * Patients with urinary tract disorder or urinary retention
  * Patient under or planning to go under electromagnetic transcranial stimulation or planning to
  * Patient unable to understand the purpose of the trial or refusing to follow treatment and post-treatment instructions
  * Patients with history of psychiatric disorder or hallucination
  * Participation to another trial that would interfere with this trial
  * Patients under legal protection

Primary outcomes:
measure: Change in pain between both treatment arms assessed by the Visual Analogic Scale (VAS)
timeFrame: 12 months
Secondary outcomes:
measure: Evaluation of Long term analgesic effect of intrathecal Ziconotide assessed by the Visual Analogic Scale (VAS)
timeFrame: 12 months
measure: Evaluation of Analgesic effect of at least 30%
timeFrame: 12 months
measure: Evaluation of Severe Adverse Events (SAE)
timeFrame: over the 12 months
measure: Evaluation of patient satisfaction with pain treatment at first visit to refill the pump (1 month) assessed by the Visual Analogic Scale (VAS)
timeFrame: 1 month
measure: Evaluation patient satisfaction of pain relief with the treatment at 6 months assessed by the Visual Analogic Scale (VAS)
timeFrame: 6 months
measure: Evaluation patient satisfaction of pain relief with the treatment 12 months assessed by the Visual Analogic Scale (VAS)
timeFrame: 12 months
measure: Analgesic effect on spontaneous pain duration
timeFrame: 1 month before initiation of treatment
measure: Analgesic effect on spontaneous pain duration
timeFrame: 6 months
measure: Analgesic effect on spontaneous pain duration
timeFrame: 12 months
measure: Analgesic effect on spontaneous pain intensity
timeFrame: 1 month before initiation of treatment
measure: Analgesic effect on spontaneous pain intensity
timeFrame: initial evaluation 6 months
measure: Analgesic effect on spontaneous pain intensity
timeFrame: initial evaluation 12 months
measure: Analgesic effect on provoked pain duration
timeFrame: initial evaluation
measure: Analgesic effect on provoked pain duration
timeFrame: 6 months
measure: Analgesic effect on provoked pain duration
timeFrame: 12 months
measure: Analgesic effect on provoked pain intensity
timeFrame: 1 month before initiation of treatment
measure: Analgesic effect on provoked pain intensity
timeFrame: 6 months
measure: Analgesic effect on provoked pain intensity
timeFrame: 12 months
measure: Quality of life at inclusion assessed by the Short Form questionnaire (SF12)
timeFrame: 1 month before initiation of treatment
measure: Quality of life at 6 months assessed by the Short Form questionnaire (SF12)
timeFrame: 6 months
measure: Quality of life at 12 months assessed by the Short Form questionnaire (SF12)
timeFrame: 12 months
measure: Patient global impression of change
timeFrame: at one months of treatment (first refill of the pump)
measure: Patient global impression of change
timeFrame: 6 months
measure: Patient global impression of change
timeFrame: 12 months
measure: Analgesic drugs intake at inclusion
timeFrame: 1 month before initiation of treatment
measure: Analgesic drugs intake at 12 months
timeFrame: 12 months
measure: Evaluation of cognition effects induced by ITZ at inclusion
timeFrame: 1 month before initiation of treatment
measure: Evaluation of cognition effects induced by ITZ at 6 months
timeFrame: 6 months
measure: Evaluation of cognition effects induced by ITZ at 12 months
timeFrame: 12 months
measure: Measure of neuro- psychological effects of depression induced by ITZ
timeFrame: 1 month before initiation of treatment
measure: Measure of neuro- psychological effects of depression induced by ITZ
timeFrame: 6 months
measure: Measure of neuro- psychological effects of depression induced by ITZ
timeFrame: 12 months
measure: Measure of neuro- psychological anxiety effects induced by ITZ
timeFrame: 1 month before initiation of treatment
measure: Measure of neuro- psychological anxiety effects induced by ITZ
timeFrame: 6 months
measure: Measure of neuro- psychological anxiety effects induced by ITZ
timeFrame: 12 months
measure: Impact of ITZ on psycho-social status of patients
timeFrame: 1 month before initiation of treatment
measure: Impact of ITZ on psycho-social status of patients
timeFrame: 6 months
measure: Impact of ITZ on psycho-social status of patients
timeFrame: 12 months
Other outcomes:
Locations:
Study officials:
affiliation: Hospices Civils de Lyon
name: MERTENS Patrick, MD, PhD
role: STUDY_DIRECTOR
References: