The primary objective of phase 1 is to validate a new ELISA measurement that can determine hIAPP oligomers reliably in plasma, and of phase 2 is to correlate pathogenic oligomer hIAPP (in plasma and skin) with pain and sensory disturbances in CIAP…
ID
Source
Brief title
Condition
- Peripheral neuropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are pathogenic oligomer hIAPP levels in plasma and
skin.
Secondary outcome
Secundary outcome measures are pain and sensory assessments using questionnaire
data, QST, intraepidermal nerve fiber (IENF) density, CPM, sublingual and skin
HVM, and neuroinflammatory markers in plasma.
Background summary
Polyneuropathy affects approximately 75-125 per 100,000 individuals, with 5-30%
classified as chronic idiopathic axonal polyneuropathy (CIAP) and 30 to 50% as
diabetic polyneuropathy (DPN). CIAP and DPN lead to progressive damage to
peripheral nerves, resulting in diverse symptoms and functional limitations.
Neuropathic pain is present in 60% of cases, negatively impacting various
quality of life domains. At present disease-modifying treatments are
unavailable, leaving patients reliant on symptom-based approaches like
anti-neuropathic drugs.
Recent findings, suggest that human islet amyloid polypeptide (hIAPP), which
can form pathogenic oligomers, is involved in the pathophysiological process of
painful DPN. We found that hIAPP-transgenic mice, which have elevated plasma
hIAPP levels without hyperglycaemia, developed peripheral neuropathy as
evidenced by pain-associated behaviour and reduced intraepidermal nerve fiber
(IENF) density. Type 2 diabetic patients had reduced IENF density and more
hIAPP oligomers in the skin compared with non-diabetic controls.
The hIAPP oligomers may also influence the microcirculation as is seen with
amyloid deposits in blood vessels in other diseases. By employing hand-held
vital microscopy (HVM) we aim to identify potential microcirculatory
inflammation and accumulation of hIAPP aggregates.
The exact relation between hIAPP and pain phenotype in DPN patients is unknown.
As CIAP has been associated with metabolic syndrome, we hypothesize a common
pathophysiological pathway in CIAP and DPN with hIAPP as a potential
disease-modifying target. In current study we will further explore this
relation between hIAPP levels in plasma and skin and pain and sensory
disturbances in CIAP and DPN patients. To investigate whether the
pathophysiological pathway involving hIAPP oligomers is specific to CIAP and
DPN, we will include a control group with patients with chronic peripheral
neuropathic pain after a varicella zoster reactivation, referred to as
postherpetic neuralgia (PHN), not associated with changes in hIAPP plasma
levels (plasma and skin samples from METC 19-099).
Study objective
The primary objective of phase 1 is to validate a new ELISA measurement that
can determine hIAPP oligomers reliably in plasma, and of phase 2 is to
correlate pathogenic oligomer hIAPP (in plasma and skin) with pain and sensory
disturbances in CIAP and DPN patients. Secondary objectives are 1) to compare
hIAPP and pathogenic oligomer hIAPP levels in plasma and skin between CIAP, DPN
and PHN patients, 2) to compare hIAPP and pathogenic oligomer hIAPP levels in
plasma and skin between CIAP and DPN patients with and without pain, 3) to
correlate pathogenic oligomer hIAPP levels with a neuroinflammatory biomarker
phenotype in CIAP and DPN patients, and 4) to monitor sublingual and skin
microcirculatory inflammation, perfusion and hIAPP oligomers using HVM, and
correlate it to a neuroinflammatory biomarker phenotype in CIAP and DPN
patients.
Study design
Observational study with invasive measurements and biobanking of residual blood
and skin after analyse.
Study burden and risks
Benefit: The obtained knowledge may contribute to more understanding of the
pathophysiology of painful polyneuropathy and may lead to the development of a
mechanism-based therapy (antibody for hIAPP developed and produced by argenx)
in the future. Patients with severe pain are offered to receive health care at
the pain clinic of the UMCU. Travel expenses will be compensated for the
hospital visit.
Disadvantages:
Patients themselves have no direct benefit from participating in this study.
Risks: The collection of blood and the skin biopsies have negligible risks .
There is no risk involved in the QST, CPM and HVM measurements as they are
non-invasive.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
o Aged 18 years or older
o Diagnosed by a neurologist with CIAP[24] based on the following criteria
o Presence of symmetrical distal sensory or sensorimotor symptoms such as
numbness, pins and needles, tightness, coldness, unsteadiness, muscle cramps,
and weakness with onset in the lower limbs, compatible with polyneuropathy
o Nerve conduction studies excluding a demyelinating polyneuropathy and
confirming large nerve fiber involvement in at least two distinct peripheral
nerves
o No identifiable cause for the polyneuropathy after thorough history-taking,
clinical examination, and extensive laboratory testing including complete blood
count, glucose, HbA1c, insulin, renal function, liver enzymes, creatine kinase,
C-reactive protein, vitamin B1, vitamin B6, folic acid, vitamin B12,
homocystein, cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and
thyroid-stimulating hormone
o Diagnosed by a physician with DPN based on the following criteria
o Diagnosed with Diabetes Mellitus Type 2 based on the NHG standard
o Presence of symmetrical distal sensory or sensorimotor symptoms such as
numbness, pins and needles, tightness, coldness, unsteadiness, muscle cramps,
and weakness with onset in the lower limbs, compatible with polyneuropathy.
o A Douleur Neuropathique en 4 (DN4)[25] questionnaire score of 4 or higher
o Able and willing to give written informed consent.
Exclusion criteria
- Patients who have other types of pain, which could confound the
assessment of the
neuropathic pain due to CIAP or DPN.
- Patient who received Capsaicin 8% patch treatment in the 3 months before
inclusion
- Patients with skin conditions in the area affected by the polyneuropathy that
could
alter sensation.
- Patients with major cognitive or psychiatric disorders.
- Problems with communication (language, deafness, aphasia etc.)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL88118.041.24 |