BotulInum Toxin Type A for Peripheral Neuropathic Pain in subjEcts With Carpal Tunnel Syndrome

BotulInum Toxin Type A for Peripheral Neuropathic Pain in subjEcts With Carpal Tunnel Syndrome: a Multicenter, Randomized, Doubleblind, Placebo-controlled Study

The main purpose of the study is to assess the safety and efficacy of repeated administrations of BoNT-A in subjects with NP attributable to carpal tunnel syndrome (CTS) through a randomized, double-blind, placebo-controlled study. Further research has shown that BoNT-A has analgesic properties independently from its action on muscle tone, possibly by acting on neurogenic inflammation. Therefore, the study drug may be better than other treatments surgical or non-surgical currently available for the treatment of CTS.

Botulinum toxin type A (BoNT-A) is widely used to treat muscle hyperactivity, based on its ability to inhibit synaptic exocytosis and, therefore, to disable neural transmission. Further research has shown that BoNT-A has analgesic properties independently from its action on muscle tone, possibly by acting on neurogenic inflammation. Animal studies indeed showed that botulinum neurotoxin can alter and alleviate NP in animals through several mechanisms, including blocking the release of pain mediators, decreasing local inflammation around nerve terminals, deactivating sodium channels, inhibiting the discharge of muscle spindles and decreasing sympathetic transmission.

Evidence on the use of BoNT-A in CTS and occipital neuralgia is still limited as it derives from small patient studies with controversial results, and is therefore considered still insufficient to determine whether or not BoNT-A could be part of the therapeutic arsenal against these NPs (level U). Overall, according to the litterature, the results of BoNT-A injections on NP are variable, as it seems to be effective in postherpetic neuralgia (evidence level A), may be effective in trigeminal neuralgia and post-traumatic neuralgia (level B) and is possibly effective in diabetic polyneuropathy (level C).

In this multicenter, randomized, double-blinding, placebo-controlled, parallel study it will enroll 164 subjects, both genders, aged ≥18 and ≤60 years old, to obtain 164 overall valuable subjects (23/24 for each center). The recruitment period (V1) will last 1 week after the baseline assessment, eligible subjects will be randomly assigned (1:1) to BoNT-A or placebo arm and will receive the first round of injections. After 12 week ±4 days (V2) subjects will undergo the second treatment round, receiving either a second BoNT-A administration or a second placebo administration. In week 24 ±4 days (V3) the same assessment scheduled for visit 1 will be repeated.

Benefit Assessment :

As described previously, BoNT-A showed some significant advantages over NPs existing treatments, such as the extended duration of its analgesic effects; BoNT-A has analgesic properties independently from its action on muscle tone, possibly by acting on neurogenic inflammation.

Therefore the study drug may be better than other treatments surgical or non-surgical currently available for the treatment of Carpal Tunnel Syndrome.

Risk Assessment :

Since it has been shown that BoNT-A has a clinically acceptable safety profile, there are no specific risks to this study.

However, considering that the drug has never been tested on patients with carpal tunnel syndrome, the objective of the study also includes the evaluation of its safety in the context of this disease.

Primary Objective

- The main objective of the study is to assess the efficacy and safety of two successive intradermal administrations of several injections of BoNT-A versus placebo, administered 12 weeks apart, in subjects with CTS and NP Secondary Objectives

The secondary objectives of this study include:

• Assessment of the therapeutic gain of BoNT-A in terms of relief of spontaneous pain.
• Assessment of BoNT-A effects in reducing neuropathic symptoms.
• Assessment of BoNT-A impact on patient's quality of life.
• Assessment of BoNT-A safety and tolerability

Statistical Hypotheses A sample size of 82 participants per group (164 participants overall) would be needed for 90% power to detect a mean difference in pain intensity between groups of 0.7 units (SD=1.3) in a two-sample two tailed t test with a type I error of 0.05, including a 10% of dropout rate. Changes in primary and secondary outcome measures (quantified measures of deficits and pains, pain scores, symptoms, quality of life) will be expressed as differences between baseline and the values obtained at each time point and will be analyzed using a generalized linear mixed-model repeated measures. For all the pre specified endpoints, the analysis will be performed in the intent-to treat population with both the last observation carried forward approach (primary analysis) and observed data (additional analysis- sensitivity). Safety data will be tabulated and where appropriate, analyzed using descriptive statistics. All tests will be two sided and a p-value of less than 0.05 will be considered as statistically significant.

Inclusion Criteria:

1. Male or female subject aged ≥18 and ≤60 years old.
2. Probable or definitive NP according to the International Association for the Study of Pain criteria.
3. Daily pain attributable to CTS for at least 6 months. This must be attributable to idiopathic carpal tunnel syndrome and with nerve conduction velocity findings consistent with this condition
4. Moderate-severe pain according to the 11-point Numerical. Rating Scale (NRS; 4-8)
5. We allow the concomitant use of analgesic treatments if they have been used at a stable doses for 4 weeks before the enrolment and for the whole study.
6. Signed informed consent prior to participation in the study

Exclusion Criteria:

1. Pain level ≥9 on 11-point NRS.
2. CTS with atrophy of median-innervated muscles and EMG study suggesting a severe nerve injury.
3. Subject with contraindications or hypersensitivity to BoNT-A.
4. Subject with disorders of the neuromuscular junction, progressive neuropathy disorders, coagulation disorders or major psychiatric disorders.
5. Subject with diabetes, rheumatoid arthritis, connective tissue diseases, vasculitis, untreated hypothyroidism, acromegaly.
6. Subject using drugs acting on neuromuscular junctions, topical drugs (e.g., capsaicin or lidocaine), or anesthetic blocks.
7. Subject has used BoNT-A.
8. Subject is pregnant or breastfeeding women.
9. Subject enrolled in another interventional trial for the treatment of of the same disease.