Amyloidosis, Carpal Tunnel Syndrome, Hereditary Transthyretin Amyloidosis, Polyneuropathy
Conditions
Keywords
ATTR PN, CTS, PN, carpal tunnel syndrome, polyneuropathy, amyloidosis
Brief summary
This is a multicenter observational study consisting of retrospective and prospective phases. The retrospective phase will entail secondary data collection from electronic or paper medical records of patients who underwent surgery for CTS to assess their probability of having ATTR PN.
Detailed description
ATTR PN is a genotypically, phenotypically and geographically variable disease with a poor prognosis, albeit available disease-modifying drugs can change the disease trajectory. Thus country-specific epidemiologic data collection and identification of early stage PN, including previously misdiagnosed patients, is crucial to improve outcomes and quality of life. However, no observational studies on the epidemiology of ATTR PN in the whole Russian population, or in patients with CTS, have been performed. Therefore, there is a need to conduct a large-scale observational study to determine the prevalence of ATTR PN in Russia, obtain information on patients' clinical characteristics, and determine their medical needs. The approaches to diagnosis of ATTR PN in Russia over the past few years have been characterized by the use of heterogenous methods, partially explained by the lack of availability of molecular genetic testing, which is essential to diagnose the presence of pathogenic mutation in patients with hereditary ATTR PN. Thus, recent introduction of such tests into routine clinical practice may allow to assess reliable epidemiologic data including estimation of true ATTR PN prevalence among patients with CTS, which can often be the first manifestation of the disease. Earlier recognition, in turn, may lead to timely treatment initiation and change in the prognostic outlook of ATTR PN patients. In order to assess the prevalence of ATTR PN in patients undergoing surgery for CTS in Russia this study will retrospectively include patients with the diagnosis of CTS undergoing surgery between the 1st January 2021 and the 1st September 2024. Suspicion of ATTR PN will be assessed in each case, and diagnostic tests (comprehensive neurological examination including nerve conduction study (NCS) combined with molecular genetic testing) to confirm or exclude the disease will be conducted prospectively in eligible patients. In addition to that, clinical features, concomitant manifestations, and diagnosed genotypes will be analyzed to examine characteristic ATTR PN patient profiles in the Russian Federation.
Interventions
None listed
Sponsors
AstraZeneca
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for the retrospective phase are: 1. Patients with the established diagnosis of CTS. 2. Bilateral involvement of carpal tunnel established between the 1st January 2021 and the 31st December 2024 (both patients who underwent CTS surgical intervention and without it are enrolled). 3. Age ≥ 18 years at the time of CTS diagnosis. 4. Provided written informed consent for the prospective phase of the study (including molecular genetic testing). 5. Presence of ≥1 of the following features (red flags): a. CIDP or polyneuropathy of unknown etiology in the family history; b. Spinal canal stenosis of the lumbar region; c. Autonomic dysfunction, defined by the presence of ≥1 of the following symptoms - i. Gastrointestinal complaints (constipation, chronic diarrhea, or both); ii. Erectile dysfunction; iii. Orthostatic hypotension; d. Gait disorders; e. Sweating disorders, anhidrosis. f. Paresthesia and burning of the skin of the distal extremities g. Distal symmetrical paresis h. Hypotrophy and hypotension of limb muscles, areflexia i. Biceps tendon rupture j. Aortic valve stenosis k. Diagnosis of HFpEF l. Unexplained weight loss ≥5 kilos at any timepoint since the onset of symptoms of CTS; m. Left ventricular hypertrophy (based on electro- or echocardiographic criteria documented in the patient's medical record); n. Heart rhythm disorders; o. Renal abnormalities, defined by ≥1 of the following features - i. Documented diagnosis of chronic kidney disease (CKD); ii. Decreased estimated glomerular filtration rate (eGFR \<60 mL/min/1.73m2); iii. Increased serum creatinine (SCr) above reference range of the local laboratory; iv. Albuminuria (≥30 mg/g of creatinine or ≥30 mg/24h); v. Proteinuria (according to urinalysis results); p. Ophthalmology disorder defined by ≥1 of the following features - i. Vitreous body inclusions (opacification); ii. Glaucoma; iii. Pupillary disorders; iv. Vitrectomy 6. Absence of previously established ATTR PN diagnosis (ICD-10 code Е85.1, "Neuropathic hereditary familial amyloidosis").
Exclusion criteria
1. Participation in any interventional trial within the period since identification of bilateral involvement of carpal tunnel until the end of current study. The following criteria apply for non-inclusion of patients into the prospective part of the study: 2. Previously performed TTR genetic testing; 3. Verified B12 deficiency; 4. History of alcohol abuse according to the patient's medical record.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To define the prevalence of ATTR PN in patients diagnosed with CTS and having bilateral involvement in routine clinical practice in the Russian Federation. | Up to 12 months | In order to achieve primary objective, the proportion of patients with confirmed diagnosis of ATTR PN (presence of TTR gene mutation according to the results of molecular genetic testing and clinical symptoms and/or signs of polyneuropathy) among those diagnosed with CTS and having bilateral involvement will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess general demographic characteristics of patients with ATTR PN in Russia - Mean age (years) at the onset of CTS symptoms | up to 12 months | — |
| To assess general demographic characteristics of patients with ATTR PN in Russia: Mean age (years) at the onset of polyneuropathy symptoms | up to 12 months | — |
| to assess general demographic characteristics of patients with ATTR PN in Russia: Proportion of patients with late (>50 years) diagnosis of ATTR PN | up to 12 months | — |
| to assess general demographic characteristics of patients with ATTR PN in Russia: Mean age (years) at the time of CTS surgery | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Number and proportion of patients with specific characteristics of the first and repeat CTS surgery | up to 12 months | 1. Left hand; 2. Right hand; 3. Both hands; |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Proportion of patients with CTS recurrence after surgery | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Proportion of patients undergoing repeat surgery for CTS after the index operation | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Proportion of patients with PN progression after surgery | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Proportion of patients with different number of red flags: | up to 12 months | 1. 1 red flag; 2. 2 red flags; 3. 3 red flags; 4. 4-5 red flags; 5. 6-10 red flags; 6. \>10 red flags; |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Mean age (years) at ATTR PN diagnosis | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Proportion of women and men | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Mean body mass index (BMI) and proportion of patients with different BMI dimensions at the time of CTS diagnosis and at Visit 1: | up to 12 months | 1. Underweight (BMI \<18.5 kg/m2); 2. Normal weight (BMI ≥18.5 and \<25 kg/m2); 3. Overweight (BMI ≥25 and \<30 kg/m2); 4. Obesity (BMI ≥30 kg/m2) |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Proportion of patients with a history of unexplained weight loss (≥5 kg) at any point since CTS diagnosis | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Mean and median time from CTS symptom onset (months) to ATTR PN diagnosis | up to 12 months | — |
| To assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Median number of physicians seen since symptom onset before the correct ATTR PN diagnosis | up to 12 months | — |
| To assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Median number of hospitalizations for PN before the correct ATTR PN diagnosis | up to 12 months | — |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Number and proportion of patients with previously established incorrect diagnosis according to medical records, specifically with: | up to 12 months | 1. CIDP; 2. Lumbar/sacral radiculopathy; 3. Lumbar canal stenosis; 4. Paraproteinaemic peripheral neuropathy; 5. Chronic progressive sensory/sensorimotor axonal idiopathic PN; 6. AL amyloidosis; 7. Fibromyalgia; 8. Other (specify) |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN: Proportion of patients with family history of neuropathic disease | up to 12 months | — |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN: Proportion of patients with specific peripheral neurological manifestations: | up to 12 months | 1. Neuropathic pain (allodynia, hyperalgesia); 2. Progressive sensory disturbances (loss of temperature, pain, other sensation); 3. Paresthesia, dysesthesia; 4. Progressive motor disturbances; 5. Walking difficulty, gait disorder; 6. Balance disorder |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN: Proportion of patients with specific Polyneuropathy Disability (PND) classes: | up to 12 months | 1. 0; 2. I; 3. II; 4. IIIA; 5. IIIB; 6. IV; |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - Proportion of patients with specific distribution of polyneuropathy symptoms: | up to 12 months | 1. Upper-limb; 2. Lower-limb; 3. Both upper-limb and lower-limb |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - Number of patients with autonomic neurological manifestations, including specifically: | up to 12 months | 1. Orthostatic hypotension; 2. Syncope; 3. Gastrointestinal motility disorders - i. Constipation; ii. Early satiety; iii. Diarrhea; iv. Nausea, vomiting; 4. Erectile dysfunction; 5. Neurogenic bladder; 6. Recurrent urinary infections; 7. Anhidrosis; |
| To describe data on the presence of cardiovascular, neurological and other comorbidities- Number and proportion of patients taking specific groups of cardiovascular medications at the time of CTS diagnosis and at the time of prospective visit: | up to 12 months | 1. Left ventricular hypertrophy; 2. Left bundle branch block; 3. Atrioventricular block; 4. Heart failure with preserved ejection fraction; 5. Elevated serum N-terminal-proB-type natriuretic peptide (NT-proBNP) concentration; 6. Cardiac valve stenosis; 7. Cardiac valve regurgitation; 8. Tachyarrhythmia; 9. Other (specify); 10. None; |
| Number of patients taking specific groups of cardiovascular medications at the time of CTS surgery and at the time of prospective visit: | up to 12 months | 1. Angiotensin converting enzyme inhibitor (ACEI) (specify); 2. Angiotensin receptor blocker (ARB) (specify); 3. Angiotensin receptor and neprilysin inhibitor (ARNI); 4. Sodium-glucose transporter type 2 inhibitor (SGLT2i) (specify); 5. Mineralocorticoid receptor antagonist (MRA) (specify); 6. Beta-blocker (specify); 7. Diuretic (specify); 8. Other cardiovascular (CV) medications (specify); 9. Other (specify); |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - Number of patients with concomitant ophthalmologic manifestations, including specifically | up to 12 months | 1. Vitreous body inclusions (opacification); 2. Glaucoma; 3. Abnormal conjunctival vessels; 4. Papillary abnormalities; 5. Dry eye; 6. Other (specify); |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - Number of patients with concomitant musculoskeletal manifestations, including specifically: | up to 12 months | 1. Spinal stenosis; 2. Osteoarthritis, including hip and knee arthroplasty; 3. Trigger finger; 4. Charcot's joints; 5. Biceps tendon rupture; 6. Rotator cuff injury; 7. Other (specify); |
| Mean and median serum NT-proBNP (pg/ml) concentration | up to 12 months | — |
| Proportion of patients with laboratory confirmed paraproteinemia | up to 12 months | — |
| Mean and median urine albumin-creatinine ratio (UACR, mg/g of creatinine) | up to 12 months | — |
| Proportion of patients with diagnosed CKD, including specifically | up to 12 months | 1. Stage C1; 2. Stage C2; 3. Stage C3a; 4. Stage C3b; 5. Stage C4; 6. Stage C5; |
| Number of patients with concomitant renal dysfunction, including specifically | up to 12 months | 1. Elevated SCr level (based on the local laboratory reference range); 2. Decreased eGFR (\<60 ml/min/1.73m2); 3. Presence of albuminuria (≥30 mg/g creatinine (≥30 mg/g of creatinine or ≥30 mg/24h); 4. Presence of proteinuria (according to urinalysis results); 5. Ultrasound signs of amyloid nephropathy; |
| Number of patients with confirmed length-dependent peripheral sensory-motor neuropathy based on NCS results | up to 12 months | — |
| Mean and median measured peripheral sensory nerve conduction velocities | up to 12 months | 1. Left Medial; 2. Left Ulnar; 3. Left Sural; 4. Right Medial; 5. Right Ulnar; 6. Right Sural; |
| Number of patients with reduced peripheral sensory nerve conduction velocity at ≥1 site | up to 12 months | — |
| Mean and median measured peripheral motor nerve conduction velocities | up to 12 months | 1. Left Medial; 2. Left Ulnar; 3. Left Tibial; 4. Left Peroneal; 5. Right Medial; 6. Right Ulnar; 7. Right Tibial; 8. Right Peroneal; |
| Number of patients with reduced motor sensory nerve conduction velocity at ≥1 site | up to 12 months | — |
| Mean and median measured sensory action potential (SAP) amplitudes | up to 12 months | 1. Left Medial; 2. Left Ulnar; 3. Left Sural; 4. Right Medial; 5. Right Ulnar; 6. Right Sural |
| Number of patients with reduced/absent SAP amplitude at ≥1 site | up to 12 months | — |
| Mean and median measured distal compound muscle action potential (dCMAP) amplitudes | up to 12 months | 1. Left Medial; 2. Left Ulnar; 3. Left Tibial; 4. Left Peroneal; 5. Right Medial; 6. Right Ulnar; 7. Right Tibial; 8. Right Peroneal |
| Mean and median measured proximal compound muscle action potential (pCMAP) amplitudes | up to 12 months | 1. Left Medial; 2. Left Ulnar; 3. Left Tibial; 4. Left Peroneal; 5. Right Medial; 6. Right Ulnar; 7. Right Tibial; 8. Right Peroneal |
| Number of patients with reduced/absent dCMAP amplitude at ≥1 site | up to 12 months | — |
| Number of patients with reduced/absent pCMAP amplitude at ≥1 site | up to 12 months | — |
| Proportion of patients with each score by each parameter of neurological examination | up to 12 months | — |
| Number of patients in the specific categories of the modified Rankin scale | up to 12 months | 1. Score 1 (no significant disability); 2. Score 2 (slight disability); 3. Score 3 (moderate disability); 4. Score 4 (moderately severe disability); 5. Score 5 (severe disability); |
| Proportion of patients with specific number of points according to Inflammatory Neuropathy Cause and Treatment (INCAT) upper extremity scale | up to 12 months | 1. 0 points; 2. 1 point; 3. 2 points; 4. 3 points; 5. 4 points; 6. 5 points |
| Median number of points according to INCAT upper extremity scale | up to 12 months | — |
| Proportion of patients with specific number of points according to INCAT lower extremity scale | up to 12 months | 1. 0 points; 2. 1 point; 3. 2 points; 4. 3 points; 5. 4 points; 6. 5 points |
| Median number of points according to INCAT lower extremity scale | up to 12 months | — |
| Mean and median number of points according to combined clinical and electrophysiological score | up to 12 months | — |
| To describe data on the results of genetic testing for ATTR in CTS patients undergoing surgery:Number and proportion of patients with specific TTR gene mutations | up to 12 months | 1. Val30Met; 2. Ile107Val; 3. Phe33Leu; 4. Ala81Val; 5. Ser23Asn; 6. Ala25Thr; 7. Val32Ala; 8. Thr40Asn; 9. Gly47Ala; 10. Glu54Gln; 11. Tyr69Phe; 12. Glu92Lys; 13. Thr119Met; 14. Other |
| to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Proportion of patients with previously established incorrect diagnosis according to medical records, specifically with: | up to 12 months | 1. CIDP; 2. Lumbar/sacral radiculopathy; 3. Lumbar canal stenosis; 4. Paraproteinaemic peripheral neuropathy; 5. Chronic progressive sensory/sensorimotor axonal idiopathic PN; 6. AL amyloidosis; 7. Fibromyalgia; 8. Other (specify); |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - proportion of patients with autonomic neurological manifestations, including specifically: | up to 12 months | manifestations, including specifically: 1. Orthostatic hypotension; 2. Syncope; 3. Gastrointestinal motility disorders - i. Constipation; ii. Early satiety; iii. Diarrhea; iv. Nausea, vomiting; 4. Erectile dysfunction; 5. Neurogenic bladder; 6. Recurrent urinary infections; 7. Anhidrosis; |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - proportion of patients with concomitant cardiac manifestations, including specifically: | up to 12 months | 1. Left ventricular hypertrophy; 2. Left bundle branch block; 3. Atrioventricular block; 4. Heart failure with preserved ejection fraction; 5. Elevated serum N-terminal-proB-type natriuretic peptide (NT-proBNP) concentration; 6. Cardiac valve stenosis; 7. Cardiac valve regurgitation; 8. Tachyarrhythmia; 9. Other (specify); 10. None; |
| proportion of patients taking specific groups of cardiovascular medications at the time of CTS surgery and at the time of prospective visit: | up to 12 months | 1. Angiotensin converting enzyme inhibitor (ACEI) (specify); 2. Angiotensin receptor blocker (ARB) (specify); 3. Angiotensin receptor and neprilysin inhibitor (ARNI); 4. Sodium-glucose transporter type 2 inhibitor (SGLT2i) (specify); 5. Mineralocorticoid receptor antagonist (MRA) (specify); 6. Beta-blocker (specify); 7. Diuretic (specify); 8. Other cardiovascular (CV) medications (specify); 9. Other (specify); |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - proportion of patients with concomitant ophthalmologic manifestations, including specifically | up to 12 months | 1. Vitreous body inclusions (opacification); 2. Glaucoma; 3. Abnormal conjunctival vessels; 4. Papillary abnormalities; 5. Dry eye; 6. Other (specify); |
| To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - proportion of patients with concomitant musculoskeletal manifestations, including specifically: | up to 12 months | 1. Spinal stenosis; 2. Osteoarthritis, including hip and knee arthroplasty; 3. Trigger finger; 4. Charcot's joints; 5. Biceps tendon rupture; 6. Rotator cuff injury; 7. Other (specify); |
| proportion of patients with concomitant renal dysfunction, including specifically | up to 12 months | 1. Elevated SCr level (based on the local laboratory reference range); 2. Decreased eGFR (\<60 ml/min/1.73m2); 3. Presence of albuminuria (≥30 mg/g creatinine (≥30 mg/g of creatinine or ≥30 mg/24h); 4. Presence of proteinuria (according to urinalysis results); 5. Ultrasound signs of amyloid nephropathy; |
| proportion of patients with confirmed length-dependent peripheral sensory-motor neuropathy based on NCS results | up to 12 months | — |
| proportion of patients with reduced peripheral sensory nerve conduction velocity at ≥1 site | up to 12 months | — |
| proportion of patients with reduced motor sensory nerve conduction velocity at ≥1 site | up to 12 months | — |
| proportion of patients with reduced/absent SAP amplitude at ≥1 site | up to 12 months | — |
| proportion of patients with reduced/absent dCMAP amplitude at ≥1 site | up to 12 months | — |
| proportion of patients with reduced/absent pCMAP amplitude at ≥1 site | up to 12 months | — |
| proportion of patients in the specific categories of the modified Rankin scale | up to 12 months | -a) Score 1 (no significant disability); b) Score 2 (slight disability); c) Score 3 (moderate disability); d) Score 4 (moderately severe disability); e) Score 5 (severe disability |
| To assess general demographic characteristics of patients with ATTR PN in Russia - Mean age (years) at the primary CTS diagnosis | up to 12 months | — |
| To assess general demographic characteristics of patients with ATTR PN in Russia - Mean age (years) at the identification of bilateral involvement | up to 12 months | — |
| To assess general demographic characteristics of patients with ATTR PN in Russia - Mean age (years) at ATTR PN diagnosis | up to 12 months | — |
| To assess general demographic characteristics of patients with ATTR PN in Russia -Proportion of patients underwent CTS surgery (i.e. at least one surgery) | up to 12 months | — |
Countries
Russia
Outcome results
None listed