Intrathecal Ziconotide Antalgic Efficacy for Severe Refractory Neuropathic

NCT ID: NCT03942848

Last Updated: 2019-05-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-20
• Study Completion Date: 2021-09-20

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.

Conditions

Severe Refractory Neuropathic Pain; Spinal Cord Lesions

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

zicotinide followed by placebo

Intervention Type: DRUG

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

Placebo followed by zicotinide

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

zicotinide followed by placebo

Intervention Type: DRUG

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

Placebo followed by zicotinide

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospices Civils de Lyon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MERTENS Patrick, MD, PhD

Role: STUDY_DIRECTOR

Hospices Civils de Lyon

Central Contacts

MERTENS Patrick, MD, PhD

Role: CONTACT

patrick.mertens@chu-lyon.fr

33 (0) 4 72 11 89 03

BERTHILLER Julien

Role: CONTACT

julien.berthiller@chu-lyon.fr

33 (0) 4 72 11 80 67

Other Identifiers

69HCL18_0034

Identifier Type: -

Identifier Source: org_study_id