Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT06225960 |
| Other study ID # |
2360CE |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 8, 2022 |
| Est. completion date |
December 2025 |
Study information
| Verified date |
January 2024 |
| Source |
Istituti Clinici Scientifici Maugeri SpA |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This is a prospective, multicenter observational study evaluating the efficacy of ganglion
stimulation (medical device) in cases of post-herpetic neuropathy.
This study introduces recent methods of phenotypic stratification of postherpetic neuropathy
into the field of interventional pain therapy. The aim is to identify which clinical
expression of this diverse pathology can derive the greatest benefits from an otherwise
effective but expensive therapy such as ganglion stimulation.
The study protocol includes the application of a common clinical practice, already in use for
several years at the promoting center and participating centers (as well as internationally
scientifically codified). It is supported by an innovative stratification of clinical
expression (phenotype of the disease), recently introduced in the literature.
The study aims to identify, through careful clinical evaluation, predictive indices of the
greatest success in invasive ganglion stimulation therapy, a treatment associated with
significant system costs and considerable inconvenience for the patient.
The results of the experimentation will allow the codification of evaluative clinical
pathways to predict a higher success index in certain clinical expressions of postherpetic
neuropathy compared to others. This will help reduce the costs of implant trials and enable
defining the real objective of the proposed therapy in consultation with the patient.
Description:
During the manifestation of varicella, the varicella-zoster virus (VZV) localizes in the
ganglia of dorsal roots or cranial nerves and remains latent until it can reactivate in
conditions of reduced immunity, such as old age or certain diseases. Infection control is
linked to cell-mediated immunity, which tends to decrease with age but can be periodically
stimulated by exposure to chickenpox or silent reactivations..
Epidemiological studies demonstrate that herpes zoster affects 5.23 cases per 1000
persons/year, with 13.7% showing signs of postherpetic neuralgia (PHN) after three months. In
individuals over 80 years, the PHN percentage rises to 80%. PHN is a very
challenging-to-treat painful syndrome with diverse manifestations in patients.
During reactivation, the virus travels along the central and peripheral dendrites of the
first neuron, reaching the skin where it causes vesicles, usually affecting a dermatome but
sometimes more than one. Post-mortem histological studies have shown atrophy of the dorsal
horns of the spinal cord and loss of cells, axons, and myelin in the dorsal root ganglion
(DRG) of patients with long-lasting PHN; histopathological changes were confined to a single
ganglion per patient. The loss of axons and myelin in sensory roots and nerves was also
present in patients without pain. In some patients, a prolonged cell-mediated inflammatory
process was evident .
Skin biopsy in PHN patients demonstrated a significant reduction in terminals of
small-caliber fibers, more evident in the epidermis than in the dermis. The innervation of
affected areas shows great variability among patients and is not correlated with pain
intensity or the degree of allodynia.
At the molecular level, increased expression of voltage-sensitive Na+ channels, alterations
in K+ channels, and an increase in transient receptor potential vanilloid 1 (TRPV1) have been
demonstrated. These modifications alter the threshold for the generation of action potentials
at the nerve terminals and can generate action potentials at the site of injury along the
fiber or at the level of the DRG. There is also a postulated loss of inhibitory GABAergic
interneurons in the dorsal horns and descending inhibition.
In a study investigating the correlation between neurophysiological tests and symptoms in
patients with ophthalmic postherpetic neuralgia (PHN), Truini and colleagues demonstrated
that the reduction in laser-evoked potentials (LEP) amplitude, due to the decrease in Aδ and
C fibers, correlated with the intensity of continuous pain. On the other hand, abnormalities
in the blink reflex, which assesses Aβ fibers, correlated with paroxysmal pain.
Neurophysiological alterations did not correlate with the presence of allodynia.
Clinically, patients may experience spontaneous pain, predominantly burning, deep and dull,
paroxysmal pain, and allodynia to mechanical and/or thermal stimuli. Some patients report
unbearable itching (9). The various manifestations of signs and symptoms in patients with PHN
suggest a spectrum of mechanisms:
1. Peripheral sensitization due to "irritable nociceptors," clinically characterized by
spontaneous and evoked pain (allodynia) and few negative signs on evaluation; b) Partial
loss of myelin and/or nerve fibers with spontaneous pain, allodynia, and areas of
sensory deficit; c) Deafferentation with spontaneous pain, severe sensory deficits
without allodynia.
In all cases, there is sensitization of second-order neurons due to an excess of
afferent impulses, modification of the connectivity of Aβ fibers, or loss of afferent
impulses (deafferentation). In cases of extensive areas of sensory deficit, there may be
a correspondence with histological pictures of widespread atrophy of dorsal horns, which
also involve the somas of second-order neurons with deafferentation of the third-order
neuron.
Treatment of Postherpetic Neuralgia (PHN) The therapy for PHN involves topical and/or
systemic pharmacological approaches with limited satisfaction, despite recent attempts
to target therapies based on phenotypic considerations. Since pain is often poorly
controlled by pharmacological treatment, various interventional neuromodulation
techniques have been proposed for PHN treatment, ranging from more peripheral approaches
(anesthetic and corticosteroid blocks on the peripheral nerve or paravertebral,
radiofrequency modulation techniques, or cryoanalgesia) to those involving the ganglion
(anesthetic and corticosteroid injection, pulsed radiofrequency modulation,
radiofrequency lesion) or at the spinal cord level (spinal cord neurostimulation, spinal
administration of drugs). The literature often reports clinical cases or case series.
Given the frequent localization of PHN pain at the trunk level, the difficulty in
achieving optimal paresthesia coverage of the pain area, and the involvement of a
limited territory to one or a few nerve roots, dorsal root ganglion (DRG) stimulation
has appeared as an interesting option in treating cases less responsive to
pharmacological therapies and less invasive pain management techniques. In a poster
presented at the first European INS congress, Pajuelo et al. reported a case series of
22 patients treated with DRG stimulation for PHN with encouraging results..
Considering the diverse clinical presentations of PHN and the underlying pathogenetic
mechanisms, it remains to be clarified which types of PHN patients are more likely to
benefit from DRG stimulation and how to identify the ganglion(s) to be treated with
neurostimulation.
- the selected patients, subsequent to a clinical evaluation confirming the
postherpetic origin of the painful condition, non-response to topical and systemic
medications, and after defining the dermatomal area of neuropathy, the option of
undergoing ganglion neurostimulation implantation will be proposed. This involves a
preliminary trial phase with the potential for definitive implantation, similar to
common clinical practice outside experimental protocols.
The trial phase involves the implantation of a ganglion electrode (or electrodes in the
case of multiple dermatomes) connected to an extracutaneous extension and linked to an
external pulse generator (EPG). During the trial phase, the patient's clinical progress
and response will be evaluated.
At the conclusion of the trial phase, in the event of a positive response from the
patient, definitive implantation will proceed through the placement of an internal pulse
generator (IPG) via subcutaneous surgery at a location chosen by the operator. The
decision for definitive implantation will be made in consultation with the patient,
following common clinical practice, without specifying precise evaluation parameters to
avoid limiting implantation opportunities for patients deciding to participate in the
protocol compared to those normally treated (right to equitable care).
T0 - Enrollment visit
After the patient signs the consent form, the following tests will be administered:
• Average minimum and maximum pain of the last month using the NRS scale (0-10)
International scale to evaluate pain intensity
- DN4 (Neuropatic Pain 4) in the validated Italian version;The items of the DN4 are
scored based on a yes (1 point) /no (0 points) answer. This leads to a score range
of 0-10 when the symptoms (range 0-7 points) as well as the signs (range 0-3
points) items are included.
- SF12 (short form health questionnaire) in the validated Italian version; The SF-12
is a self-reported outcome measure assessing the impact of health on an
individual's everyday life. It is often used as a quality of life measure
- EQ5 (Euro QOL 5) in the validated Italian version. EQ-5D is an instrument which
evaluates the generic quality of life developed in Europe
In clinical examination, in accordance with the latest guidelines (14) for
stratification through the evaluation of the sensory profile of patients with
neuropathic pain, three categories (clusters) of patients will be identified:
- "sensory loss": a signal of loss of small and large fibers, previously defined as
deafferentation or hypoesthesia symptoms.
- "thermal hyperalgesia": a sign of predominantly preserved large-diameter fibers and
hyperalgesic response to heat and cold (previously described as "irritated
nociceptor").
- "mechanical hyperalgesia": loss of sensitivity to heat and cold due to small fiber
deficits associated with pressure and pinprick hyperalgesia.
At the end of this initial phase, depending on the enrolling center's clinical practice,
the patient will be offered either an anesthetic block or pulsed ganglion
neuromodulation to assess the patient's response. In the case of a clinically positive
response, indicating short-term pain reduction or patient satisfaction (positive test
but ineffective therapy), patients will be offered ganglion electrode implantation.
T1: Ganglion electrode implantation (trial phase) During the trial phase, if the
patient's dermatomal area has not been previously mapped using block and radiofrequency
techniques, the level or levels of correspondence during sensory stimulation and the
placement of the ganglion electrode will be evaluated. The definitive placement will be
one where the electrode or electrodes are capable of generating "paresthesia" throughout
the patient's painful area. In case it is not possible to achieve complete coverage
(noting the reasons for such lack and estimating the percentage coverage), the ganglion
electrode will be placed in the best possible position. If it is necessary to position
the electrode catheters above and below the metamere (so-called "belting"), the patient
will be considered a drop-out.
T2: Evaluation of the trial phase at 1 month • Average minimum and maximum pain of the
last month using the NRS scale (0-10);
• DN4 (neuropathic pain) in the validated Italian version;
• SF12 (short form health questionnaire) in the validated Italian version;
• EQ5 (Euro QOL 5) in the validated Italian version;
• PGIC (Patient Global Impression Change) with 7 items. T3: Clinical evaluation at 6
months (primary endpoint)
At 6 months, patients who underwent definitive implantation will be administered the
following tests by the physicians participating in the study:
• Average minimum and maximum pain of the last month using the NRS scale (0-10);
- DN4 (neuropathic pain) in the validated Italian version;
- SF12 (short form health questionnaire) in the validated Italian version;
- EQ5 (Euro QOL 5) in the validated Italian version;
- PGIC (Patient Global Impression Change) with 7 items. .
T4: Clinical evaluation at 12 months:
At 12 months, patients who underwent definitive implantation will be administered the
following tests by the physicians participating in the study:
- Average minimum and maximum pain of the last month using the NRS scale (0-10);
- DN4 (neuropathic pain) in the validated Italian version;
- SF12 (short form health questionnaire) in the validated Italian version;
- EQ5 (Euro QOL 5) in the validated Italian version;
- PGIC (Patient Global Impression Change) with 7 items. The patient will also be
reassessed by the physician who performed the initial evaluation to determine
changes in response to the objective examination (pin-prick test, heat, cold,
touch). In case of system removal between the 6th and 12th month, the reasons for
removal (loss of efficacy, intolerance, etc.) will be recorded.
