Marsili Syndrome as a Gateway to Novel Analgesic Targets

NCT07755930 | Not Yet Recruiting DMC

• 1 other identifier: N-20260041
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

Congenital insensitivity to pain (CIP) comprises a group of rare genetic disorders caused by mutations in genes essential for pain sensing in humans. Among these, Marsili syndrome is caused by a dominant point mutation in the transcription factor ZFHX2, and it is characterized by markedly reduced sensitivity to noxious heat, mechanical injury, while other functions remain intact. this project aims to establish the first integrated, system-level characterization of Marsili syndrome by combining human sensory phenotyping with neurophysiological and molecular analyses. The study will be conducted in two sessions of approximately 4 hours each, 24 hours apart from each other

Conditions

Marsili Syndrome

Outcome Measures

Primary Outcomes (29)

• Measuring pain by computerized Visual Analog Scale Scoring

  We will ask the subjects to rate the sensation of pain on a scale from 0 to100, where 0 represents no pain and 100 represent the worst imaginable pain.

  Day 1

• Measuring pain by computerized Visual Analog Scale Scoring

  We will ask the subjects to rate the sensation of pain on a scale from 0 to100, where 0 represents no pain and 100 represent the worst imaginable pain.

  Day 2

• Measuring Itch by computerized Visual Analog Scale Scoring

  We will ask the subjects to rate the sensation of itch on a scale from 0 to100, where 0 represents no itch and 100 represent the worst imaginable itch.

  Day 1

• Measuring Itch by computerized Visual Analog Scale Scoring

  We will ask the subjects to rate the sensation of itch on a scale from 0 to100, where 0 represents no itch and 100 represent the worst imaginable itch.

  Day 2

• Alloknesis

  Measured using a standardized sensory brush exerting a force of 200 to 400 mN.

  Day 1

• Alloknesis

  Measured using a standardized sensory brush exerting a force of 200 to 400 mN.

  Day 2

• Mechanically evoked itch (MEI)

  MEI is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).

  Day 1

• Mechanically evoked itch (MEI)

  MEI is measured by using mildly pruritic, non-painful von Frey nylon filaments of a predetermined intensity (generally 5-30 miliNewton of force).

  Day 2

• Mechanical Pain Thresholds (MPT)

  This test is conducted using a pinprick set. The set consists of 7 needles each with a diameter of 0.6 mm and different force applications: 8, 16, 32, 64, 128, 256, and 512 mN.

  Day 1

• Mechanical Pain Thresholds (MPT)

  This test is conducted using a pinprick set. The set consists of 7 needles each with a diameter of 0.6 mm and different force applications: 8, 16, 32, 64, 128, 256, and 512 mN.

  Day 2

• Mechanical Pain Sensitivity (MPS)

  This test is conducted with the same pinprick set used to test the MPT.

  Day 2

• Mechanical Pain Sensitivity (MPS)

  This test is conducted with the same pinprick set used to test the MPT.

  Day 1

• Pressure Pain Threshold

  Pressure pain threshold (PPT) is obtained using a manual pressure algometer

  Day 1

• Pressure Pain Threshold

  Pressure pain threshold (PPT) is obtained using a manual pressure algometer

  Day 2

• Mechanical Suprathreshold Pain Stimulation

  Once PPT has been determined, stimuli of 130% of the PPT will be delivered to the limb or shoulder to create a sensation of subjective mild/moderate pain

  Day 2

• Computerized Cuff Pressure Algometer (CPA)

  A computer-controlled cuff pressure algometer works by inflating a cuff/tourniquet, which is similar in design to those used for measuring blood pressure

  Day 1

• Spatial and Temporal Summation of Pain

  Spatial and temporal summation of pain will be assessed with the use of the computerized cuff pressure algometer

  Day 1

• Cold Detection Thresholds (CDT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 1

• Cold Detection Thresholds (CDT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 2

• Warm Detection Thresholds (WDT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 1

• Warm Detection Thresholds (WDT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 2

• Cold Pain Thresholds (CPT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 1

• Cold Pain Thresholds (CPT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 2

• Heat Pain Thresholds (HPT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 1

• Heat Pain Thresholds (HPT)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 2

• Pain to Supra-threshold Heat Stimuli (STHS)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 1

• Pain to Supra-threshold Heat Stimuli (STHS)

  The tests of thermal sensation will all be conducted using a PATHWAY ATS (Medoc Ltd, Israel) thermal sensory testing device

  Day 2

• EEG recording

  The EEG signal will be acquired constantly through 64 electrodes placed on the scalp according to the international 10-20 system with a standard EEG cap

  Day 1

• Measuring cortical responses to magnetic stimulation

  Transcranial magnetic stimulation (TMS) will be used to evoke cortical responses (TMSevoked potentials - TEPs) in the left and right motor cortex with a figure-eight-shaped cone coil (200 pulses for each target).

  Day 1

Secondary Outcomes (15)

• Superficial blood perfusion

  Day 1

• Superficial blood perfusion

  Day 2

• Pain Catastrophizing Scale (PCS).

  Baseline

• Itch Catastrophizing Scale (ICS).

  Baseline

• Reinforcement Sensitivity Theory - Personality Questionnaire (RST-PQ).

  Baseline

Other Outcomes (3)

• Genomic DNA isolation

  Baseline

• MicroRNA assessment

  Baseline

• Proteome assessment

  Baseline

Study Arms (1)

Marsili group

EXPERIMENTAL

Other: Histamine; Other: Cowhage (Mucuna Pruriens); Drug: Capsaicin 8% Patch; Other: Knee Injections of hypertonic saline; Other: Cold Pressure Test; Other: Computerized Conditioned Pain Modulation (CPM)

Interventions

Histamine OTHER

To deliver histamine, standard allergy skin prick test (SPT) lancets are applied

Marsili group

Cowhage (Mucuna Pruriens) OTHER

The spicules will be manually inserted. Approximately 30-35 spicules are gently rubbed into a 1 cm diameter skin area on the forearm

Marsili group

Capsaicin 8% Patch DRUG

Capsaicin patches (2x2 cm, dosage form: transdermal patch 8%) will be applied on the selected area. The patch will be left in place for 30 minutes after which it will be removed.

Marsili group

Knee Injections of hypertonic saline OTHER

Experimental knee pain will be induced with a 0.25-0.30 mL bolus injection of 5% hypertonic saline, which will be injected into the dominant Infrapatellar Fat Pad (IFP)

Marsili group

Cold Pressure Test OTHER

Participants will be asked to place their hand in the cold-water tank (temperature around 5°C) and to keep it for as long as they can tolerate it.

Marsili group

Computerized Conditioned Pain Modulation (CPM) OTHER

CPM will be assessed using a double-cuff.

Marsili group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy men and women aged 18-80 years
• Marsili syndrome
• Speak and understand English

You may not qualify if:

• Pregnant or breastfeeding
• Current regular use of cannabis, opioids, cocaine, amphetamines, MDMA/ecstasy, benzodiazepines, barbiturates, hallucinogens, or other central nervous system-active recreational drugs.
• Current use of prescription medication that may significantly affect pain perception, itch perception, cortical excitability, or inflammatory responses, including opioids, antiepileptic drugs, antidepressants, antipsychotics, systemic corticosteroids, or immunosuppressive medication.
• Current or previous neurological disease, including epilepsy, stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, Parkinson's disease, or other degenerative neurological disorders.
• Current or previous severe psychiatric disorder, including major depression, psychosis, bipolar disorder, or severe anxiety disorder.
• Current or previous clinically significant musculoskeletal, cardiovascular, pulmonary, inflammatory, autoimmune, or dermatological disease that may interfere with study procedures or outcome measures.
• Lack of ability to understand study information, provide informed consent, or cooperate with study procedures.
• Abnormally disrupted sleep during the 24 hours before the experiment.
• Contraindications to TMS, including previous epileptic seizure, implanted electronic medical devices, metal implants in the head or jaw, implanted hearing aids, facial metal implants, permanent makeup, or tattoos in the facial area.
• Inability to pass the Transcranial Magnetic Stimulation Adult Safety Screen.
• Abnormally disrupted sleep in the 24 hours preceding the experiment

Sponsors & Collaborators

• Aalborg University: lead

Study Sites (1)

Center for Neuroplasticity and Pain Faculty of Medicine, Aalborg University Selma Lagerløfs Vej 249 9260 Gistrup, Denmark

Gistrup, Aalborg, 9260, Denmark

Location

MeSH Terms

Interventions

Histamine; Capsaicin; Transdermal Patch

Intervention Hierarchy (Ancestors)

Biogenic Monoamines; Biogenic Amines; Amines; Organic Chemicals; Ethylamines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Autacoids; Inflammation Mediators; Biological Factors; Polyunsaturated Alkamides; Amides; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Solanaceous Alkaloids; Alkaloids; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Equipment and Supplies

Central Study Contacts

Silvia Lo Vecchio

CONTACT

21397785; slv@hst.aau.dk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate professor

Study Record Dates

• First Submitted: July 31, 2026
• First Posted: August 10, 2026
• Study Start: August 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: August 10, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)