Intrathecal Ziconotide Antalgic Efficacy for Severe Refractory Neuropathic (SPIDOL)

Assessment of Intrathecal Ziconotide Antalgic Efficacy for Severe Refractory Neuropathic Pain Due to Spinal Cord Lesions.

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.

Study Overview

• Status: Unknown
• Conditions: Severe Refractory Neuropathic Pain; Spinal Cord Lesions
• Intervention / Treatment: Drug: zicotinide followed by placebo; Drug: Placebo followed by zicotinide

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intrathecal Ziconotide followed by placebo; Each of the 44 patients will receive alternatively treatment or placebo, for 6 months. The treatment for each period will be randomly assigned. A washout period of 15 days will be applied between the two periods of infusion.	Drug: zicotinide followed by placebo; The experimental treatment period consists of Ziconotide solution that will be prepared by each local pharmacy team, in 5 or 10 milliliter (ml) vials with constant concentration of 10micrograms/mL; Drug: Placebo followed by zicotinide; The placebo treatment period consists in standard saline solution (preservative-free sodium chloride 9 milligram/milliliter (mg/ml) (0.9%) solution) which will be presented exactly in vials as presented for the treatment (volume, color, shape et size of the vial). Treating physicians will not be aware of the actual contents of the pump and will increase the volume of injected placebo as a treatment solution (as Ziconotide 10 micrograms/milliliter (μg/ml). The magnitude of increase is the decision of the treating physician (as long as it remains with the recommended limits by the Hospital Anxiety and Depression Scale (HAS) but most likely augmentations will be at maximum 1 microgram per month and maximum achieved doses allowed in SPIDOL study is 20 micrograms/day (in literature approximately 75% of patients who respond satisfactorily to treatment required a dose of ≤ 9.6 micrograms/day
Placebo Comparator: intrathecal Ziconotide preceded by placebo; Each of the 44 patients will receive alternatively treatment or placebo, for 6 months. The treatment for each period will be randomly assigned. A washout period of 15 days will be applied between the two periods of infusion.	Drug: zicotinide followed by placebo; The experimental treatment period consists of Ziconotide solution that will be prepared by each local pharmacy team, in 5 or 10 milliliter (ml) vials with constant concentration of 10micrograms/mL; Drug: Placebo followed by zicotinide; The placebo treatment period consists in standard saline solution (preservative-free sodium chloride 9 milligram/milliliter (mg/ml) (0.9%) solution) which will be presented exactly in vials as presented for the treatment (volume, color, shape et size of the vial). Treating physicians will not be aware of the actual contents of the pump and will increase the volume of injected placebo as a treatment solution (as Ziconotide 10 micrograms/milliliter (μg/ml). The magnitude of increase is the decision of the treating physician (as long as it remains with the recommended limits by the Hospital Anxiety and Depression Scale (HAS) but most likely augmentations will be at maximum 1 microgram per month and maximum achieved doses allowed in SPIDOL study is 20 micrograms/day (in literature approximately 75% of patients who respond satisfactorily to treatment required a dose of ≤ 9.6 micrograms/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain between both treatment arms assessed by the Visual Analogic Scale (VAS)	The primary endpoint is the comparison, for each patient, of the mean pain intensity, within the last two week before the end of treatment, between two conditions: under Intrathecal Ziconotide (ITZ) and intrathecal (IT) placebo, using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain and 10 being the highest level of pain.The final endpoint will be measured after 6 months of treatment and 6 months of placebo (or vice versa according to the random assignation of first treatment in this cross over design study), that is to say after a total of 12 months of treatment.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of Long term analgesic effect of intrathecal Ziconotide assessed by the Visual Analogic Scale (VAS)	Continuous evaluation of pain intensity will be assessed using a visual analogic scale during the 12 months of treatment. Pain intensity will be measured using visual analogic scale (VAS). This VAS is a graduated line from 0 to 10 with 0 being the lowest level of pain and 10 being the highest level of pain . The patient identifies his level of pain on this graduated line.	12 months
Evaluation of Analgesic effect of at least 30%	Percentage of patients with at least 30% of pain reduction base on numeric scale within the last week before the end of treatment. Pain intensity will be measured using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain and 10 being the highest level of pain. The patient identifies his level of pain on this graduated line.	12 months
Evaluation of Severe Adverse Events (SAE)	Declaration of all severe adverse event occurring during the 12 months period of treatment. Each event will be analyzed by an independent committee to evaluate the immutability of the experimental treatment.	over the 12 months
Evaluation of patient satisfaction with pain treatment at first visit to refill the pump (1 month) assessed by the Visual Analogic Scale (VAS)	Satisfaction level of patient's pain relief will be assessed using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of satisfaction and 10 being the highest satisfaction. The patient identifies his level of satisfaction of pain relief on this graduated line.	1 month
Evaluation patient satisfaction of pain relief with the treatment at 6 months assessed by the Visual Analogic Scale (VAS)	Satisfaction level of patient's pain relief will be assessed using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of satisfaction and 10 being the highest satisfaction. The patient identifies his level of satisfaction of pain relief on this graduated line.	6 months
Evaluation patient satisfaction of pain relief with the treatment 12 months assessed by the Visual Analogic Scale (VAS)	Satisfaction level of patient's pain relief will be assessed using visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of satisfaction and 10 being the highest satisfaction. The patient identifies his level of satisfaction of pain relief on this graduated line.	12 months
Analgesic effect on spontaneous pain duration	Duration (average time per day)	1 month before initiation of treatment
Analgesic effect on spontaneous pain duration	Duration (average time per day)	6 months
Analgesic effect on spontaneous pain duration	Duration (average time per day)	12 months
Analgesic effect on spontaneous pain intensity	Intensity of spontaneous pain will be assessed using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of intensity of pain and 10 being the highest intensity of pain. The patient identifies his level of pain intensity on this graduated line.	1 month before initiation of treatment
Analgesic effect on spontaneous pain intensity	intensity (numeric scale) of spontaneous pain. This numeric scale is a graduated line from 0 to 10, 0 being the lowest level of intensity of pain and 10 being the highest intensity of pain. T The patient identifies his level of pain intensity on this graduated line.	initial evaluation 6 months
Analgesic effect on spontaneous pain intensity	intensity (numeric scale) of spontaneous pain. This numeric scale is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity. The patient identifies his level of pain intensity on this graduated line.	initial evaluation 12 months
Analgesic effect on provoked pain duration	Duration (average time per day)	initial evaluation
Analgesic effect on provoked pain duration	Duration (average time per day)	6 months
Analgesic effect on provoked pain duration	Duration (average time per day)	12 months
Analgesic effect on provoked pain intensity	Intensity of provoked pain will be assessed using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity.	1 month before initiation of treatment
Analgesic effect on provoked pain intensity	intensity of provoked pain will be assessed using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity.	6 months
Analgesic effect on provoked pain intensity	intensity of provoked pain will be assessed using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity.	12 months
Quality of life at inclusion assessed by the Short Form questionnaire (SF12)	Quality of life will be assessed using the 12 items Short Form questionnaire (SF12). It is a self-reported multipurpose questionnaire generic measure of health status. It measure in 12 questions, 8 concepts: physical functioning, role limitation due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems and mental health. A specific algorithm gives a standardized total score between 0 and 100 for physical and mental summary scale. The higher the score, the better the quality of life.	1 month before initiation of treatment
Quality of life at 6 months assessed by the Short Form questionnaire (SF12)	Quality of life will be assessed using the 12 items Short Form questionnaire (SF12). It is a self-reported multipurpose questionnaire generic measure of health status. It measure in 12 questions, 8 concepts: physical functioning, role limitation due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems and mental health. A specific algorithm gives a standardized total score between 0 and 100 for physical and mental summary scale. The higher the score, the better the quality of life.	6 months
Quality of life at 12 months assessed by the Short Form questionnaire (SF12)	Quality of life will be assessed using the 12 items Short Form questionnaire (SF12). It is a self-reported multipurpose questionnaire generic measure of health status. It measure in 12 questions, 8 concepts: physical functioning, role limitation due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems and mental health. A specific algorithm gives a standardized total score between 0 and 100 for physical and mental summary scale. The higher the score, the better the quality of life.	12 months
Patient global impression of change	Patient global impression of change estimated using a using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity.	at one months of treatment (first refill of the pump)
Patient global impression of change	Patient global impression of change estimated using a using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity.	6 months
Patient global impression of change	Patient global impression of change estimated using a visual analogic scale (VAS). This VAS is a graduated line from 0 to 10, 0 being the lowest level of pain intensity and 10 being the highest pain intensity.	12 months
Analgesic drugs intake at inclusion	Quantification of analgesic drugs intake per day with differentiation of class of analgesics.	1 month before initiation of treatment
Analgesic drugs intake at 12 months	Quantification of analgesic drugs intake per day with differentiation of class of analgesics.	12 months
Evaluation of cognition effects induced by ITZ at inclusion	Mini Mental State Examination (MMSE) questionnaire will be used to evaluate cognition effect. Each 30 questions is one point. Patients with score greater than 27 has no mental issue, between 24 et 27 light dementia, less than 24 dementia.	1 month before initiation of treatment
Evaluation of cognition effects induced by ITZ at 6 months	Mini Mental State Examination (MMSE) questionnaire will be used to evaluate cognition effect. Each 30 questions is one point. Patients with score greater than 27 has no mental issue, between 24 et 27 light dementia, less than 24 dementia.	6 months
Evaluation of cognition effects induced by ITZ at 12 months	Mini Mental State Examination (MMSE) questionnaire will be used to evaluate cognition effect. Each 30 questions is one point. Patients with score greater than 27 has no mental issue, between 24 et 27 light dementia, less than 24 dementia.	12 months
Measure of neuro- psychological effects of depression induced by ITZ	Hospital Anxiety and Depression Scale (HADS) for depression include 7 questions with a score from 0 to 3. If the score is greater than 11 then the patient suffer from depression	1 month before initiation of treatment
Measure of neuro- psychological effects of depression induced by ITZ	Hospital Anxiety and Depression Scale (HADS) for depression include 7 questions with a score from 0 to 3. If the score is greater than 11 then the patient suffer from depression	6 months
Measure of neuro- psychological effects of depression induced by ITZ	Hospital Anxiety and Depression Scale (HADS) for depression include 7 questions with a score from 0 to 3. If the score is greater than 11 then the patient suffer from depression	12 months
Measure of neuro- psychological anxiety effects induced by ITZ	Hospital Anxiety and Depression Scale (HADS) for anxiety include 7 questions with a score from 0 to 3. If the score is greater than 11 then the patient suffer from anxiety.	1 month before initiation of treatment
Measure of neuro- psychological anxiety effects induced by ITZ	Hospital Anxiety and Depression Scale (HADS) for anxiety include 7 questions with a score from 0 to 3. If the score is greater than 11 then the patient suffer from anxiety.	6 months
Measure of neuro- psychological anxiety effects induced by ITZ	Hospital Anxiety and Depression Scale (HADS) for anxiety include 7 questions with a score from 0 to 3. If the score is greater than 11 then the patient suffer from anxiety.	12 months
Impact of ITZ on psycho-social status of patients	Pain catastrophizing scale (PCS) score to assess the patient's physical and emotional distress associated with their pain condition. The scale is composed of 13 questions with a score for each questions going from 0 to 4. The final score is the addition of the score of each question, going from 0 to 52. Patient with a score greater than the 75% percentile mean value is at high risk of pain chronicity. Patient with a score between the 50 % and 75% percentile mean value is at moderate risk of pain chronicity	1 month before initiation of treatment
Impact of ITZ on psycho-social status of patients	Pain catastrophizing scale (PCS) score to assess the patient's physical and emotional distress associated with their pain condition. The scale is composed of 13 questions with a score for each questions going from 0 to 4. The final score is the addition of the score of each question, going from 0 to 52. Patient with a score greater than the 75% percentile mean value is at high risk of pain chronicity. Patient with a score between the 50 % and 75% percentile mean value is at moderate risk of pain chronicity	6 months
Impact of ITZ on psycho-social status of patients	Pain catastrophizing scale (PCS) score to assess the patient's physical and emotional distress associated with their pain condition. The scale is composed of 13 questions with a score for each questions going from 0 to 4. The final score is the addition of the score of each question, going from 0 to 52. Patient with a score greater than the 75% percentile mean value is at high risk of pain chronicity. Patient with a score between the 50 % and 75% percentile mean value is at moderate risk of pain chronicity	12 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Study Director: MERTENS Patrick, MD, PhD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Anticipated): June 20, 2019
• Primary Completion (Anticipated): December 20, 2019
• Study Completion (Anticipated): September 20, 2021

Study Registration Dates

• First Submitted: May 18, 2018
• First Submitted That Met QC Criteria: May 7, 2019
• First Posted (Actual): May 8, 2019

Study Record Updates

• Last Update Posted (Actual): May 8, 2019
• Last Update Submitted That Met QC Criteria: May 7, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: ziconotide; refractory neuropathic pain; Spinal cord lesion; intrathecal infusion
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia
• Other Study ID Numbers: 69HCL18_0034

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No