Hereditary Transthyretin Amyloidosis Polyneuropathy in Patients With Carpal Tunnel Syndrome in Russia

Carpal Tunnel Syndrome Clinical Trial

— LOCUS  

Official title:

A Multicenter Observational Retrospective-prospective Study of Prevalence, Clinical Characteristics of Hereditary Transthyretin Amyloidosis Polyneuropathy in Russian Patients Undergoing Surgery for CTS in Real Clinical Practice

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06414746
• Other study ID #: D8451R00001
• Status: Recruiting
• Start date: December 29, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 880
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

for the retrospective phase are:

1. Patients with the established diagnosis of CTS undergoing surgical intervention between the 1st January 2021 and the 1st September 2024.

2. Age = 18 years at the time of surgery.

Additional inclusion criteria for the prospective phase are:

3. Provided written informed consent for the prospective phase of the study (including molecular genetic testing).

4. Bilateral CTS;

5. Presence of =1 of the following features (red flags):

1. CIDP or polyneuropathy of unknown etiology in the family history;

2. Spinal canal stenosis of the lumbar region;

3. 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;

4. Gait disorders;

5. Sweating disorders, anhidrosis.

6. Paresthesia and burning of the skin of the distal extremities

7. Distal symmetrical paresis

8. Hypotrophy and hypotension of limb muscles, areflexia

9. Biceps tendon rupture

10. Aortic valve stenosis

11. Diagnosis of HFpEF

12. Unexplained weight loss =5 kilos at any timepoint since the onset of symptoms of CTS;

13. Left ventricular hypertrophy (based on electro- or echocardiographic criteria documented in the patient's medical record);

14. Heart rhythm disorders;

15. 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).

16. 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 ?85.1, "Neuropathic hereditary familial amyloidosis").

Exclusion Criteria:

for the retrospective phase are:

1. Participation in any interventional trial within the period since surgical intervention until the end of current study.

Additional exclusion criteria for the prospective phase are:

2. Previously performed TTR genetic testing;

3. Verified B12 deficiency;

4. History of alcohol abuse according to the patient's medical record.

Related Conditions & MeSH terms

• Amyloid Neuropathies
• Amyloid Neuropathies, Familial
• Amyloidosis
• Carpal Tunnel Syndrome
• Hereditary Transthyretin Amyloidosis
• Polyneuropathies
• Polyneuropathy
• Syndrome

Locations

Country	Name	City	State
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint-Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To define the prevalence of ATTR PN in patients undergoing surgery for CTS in routine clinical practice in the Russian Federation	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 who underwent surgery for CTS will be calculated.	Up to 12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Number and proportion of patients with specific characteristic of index CTS download	Left hand; Right hand; Both hands; First procedure; Second and later procedures	up to 12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Proportion of patients with different number of red flags:	1 red flag; 2 red flags; 3 red flags; 4-5 red flags; 6-10 red flags; >10 red flags;	up to 12 months
Secondary	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
Secondary	to assess general demographic and clinical characteristics of patients with ATTR PN in Russia: Proportion of women and men		up to 12 months
Secondary	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 surgery and at Visit 1:	Underweight (BMI <18.5 kg/m2); Normal weight (BMI =18.5 and <25 kg/m2); Overweight (BMI =25 and <30 kg/m2); Obesity (BMI =30 kg/m2)	up to 12 months
Secondary	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 symptom onset		up to 12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	to assess general demographic and clinical characteristics of patients with ATTR PN in Russia - Number of patients with previously established incorrect diagnosis according to medical records, specifically with:	CIDP; Lumbar/sacral radiculopathy; Lumbar canal stenosis; Paraproteinaemic peripheral neuropathy; Chronic progressive sensory/sensorimotor axonal idiopathic PN; AL amyloidosis; Fibromyalgia; Other (specify)	up to 12 months
Secondary	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
Secondary	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:	Neuropathic pain (allodynia, hyperalgesia); Progressive sensory disturbances (loss of temperature, pain, other sensation); Paresthesia, dysesthesia; Progressive motor disturbances; Walking difficulty, gait disorder; Balance disorder	up to 12 months
Secondary	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:	0; I; II; IIIA; IIIB; IV;	up to 12 months
Secondary	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:	Upper-limb; Lower-limb; Both upper-limb and lower-limb	up to 12 months
Secondary	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:	Orthostatic hypotension; Syncope; Gastrointestinal motility disorders - i. Constipation; ii. Early satiety; iii. Diarrhea; iv. Nausea, vomiting; Erectile dysfunction; Neurogenic bladder; Recurrent urinary infections; Anhidrosis;	up to 12 months
Secondary	To describe data on the presence of cardiovascular, neurological and other comorbidities in Russian patients with ATTR PN - Number of patients with concomitant cardiac manifestations, including specifically:	Left ventricular hypertrophy; Left bundle branch block; Atrioventricular block; Heart failure with preserved ejection fraction; Elevated serum N-terminal-proB-type natriuretic peptide (NT-proBNP) concentration; Cardiac valve stenosis; Cardiac valve regurgitation; Tachyarrhythmia; Other (specify); None;	up to 12 months
Secondary	Number of patients taking specific groups of cardiovascular medications at the time of CTS surgery and at the time of prospective visit:	Angiotensin converting enzyme inhibitor (ACEI) (specify); Angiotensin receptor blocker (ARB) (specify); Angiotensin receptor and neprilysin inhibitor (ARNI); Sodium-glucose transporter type 2 inhibitor (SGLT2i) (specify); Mineralocorticoid receptor antagonist (MRA) (specify); Beta-blocker (specify); Diuretic (specify); Other cardiovascular (CV) medications (specify); Other (specify);	up to 12 months
Secondary	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	Vitreous body inclusions (opacification); Glaucoma; Abnormal conjunctival vessels; Papillary abnormalities; Dry eye; Other (specify);	up to 12 months
Secondary	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:	Spinal stenosis; Osteoarthritis, including hip and knee arthroplasty; Trigger finger; Charcot's joints; Biceps tendon rupture; Rotator cuff injury; Other (specify);	up to 12 months
Secondary	Mean and median serum NT-proBNP (pg/ml) concentration		up to 12 months
Secondary	Proportion of patients with laboratory confirmed paraproteinemia		up to 12 months
Secondary	Mean and median urine albumin-creatinine ratio (UACR, mg/g of creatinine)		up to 12 months
Secondary	Proportion of patients with diagnosed CKD, including specifically	Stage C1; Stage C2; Stage C3a; Stage C3b; Stage C4; Stage C5;	up to 12 months
Secondary	Number of patients with concomitant renal dysfunction, including specifically	Elevated SCr level (based on the local laboratory reference range); Decreased eGFR (<60 ml/min/1.73m2); Presence of albuminuria (=30 mg/g creatinine (=30 mg/g of creatinine or =30 mg/24h); Presence of proteinuria (according to urinalysis results); Ultrasound signs of amyloid nephropathy;	up to 12 months
Secondary	Number of patients with confirmed length-dependent peripheral sensory-motor neuropathy based on NCS results		up to 12 months
Secondary	Mean and median measured peripheral sensory nerve conduction velocities	Left Medial; Left Ulnar; Left Sural; Right Medial; Right Ulnar; Right Sural;	up to 12 months
Secondary	Number of patients with reduced peripheral sensory nerve conduction velocity at =1 site		up to 12 months
Secondary	Mean and median measured peripheral motor nerve conduction velocities	Left Medial; Left Ulnar; Left Tibial; Left Peroneal; Right Medial; Right Ulnar; Right Tibial; Right Peroneal;	up to 12 months
Secondary	Number of patients with reduced motor sensory nerve conduction velocity at =1 site		up to 12 months
Secondary	Mean and median measured sensory action potential (SAP) amplitudes	Left Medial; Left Ulnar; Left Sural; Right Medial; Right Ulnar; Right Sural	up to 12 months
Secondary	Number of patients with reduced/absent SAP amplitude at =1 site		up to 12 months
Secondary	Mean and median measured distal compound muscle action potential (dCMAP) amplitudes	Left Medial; Left Ulnar; Left Tibial; Left Peroneal; Right Medial; Right Ulnar; Right Tibial; Right Peroneal	up to 12 months
Secondary	Mean and median measured proximal compound muscle action potential (pCMAP) amplitudes	Left Medial; Left Ulnar; Left Tibial; Left Peroneal; Right Medial; Right Ulnar; Right Tibial; Right Peroneal	up to 12 months
Secondary	Number of patients with reduced/absent dCMAP amplitude at =1 site		up to 12 months
Secondary	Number of patients with reduced/absent pCMAP amplitude at =1 site		up to 12 months
Secondary	Proportion of patients with each score by each parameter of neurological examination		up to 12 months
Secondary	Number of patients in the specific categories of the modified Rankin scale	Score 1 (no significant disability); Score 2 (slight disability); Score 3 (moderate disability); Score 4 (moderately severe disability); Score 5 (severe disability);	up to 12 months
Secondary	Proportion of patients with specific number of points according to Inflammatory Neuropathy Cause and Treatment (INCAT) upper extremity scale	0 points; 1 point; 2 points; 3 points; 4 points; 5 points	up to 12 months
Secondary	Median number of points according to INCAT upper extremity scale		up to 12 months
Secondary	Proportion of patients with specific number of points according to INCAT lower extremity scale	0 points; 1 point; 2 points; 3 points; 4 points; 5 points	up to 12 months
Secondary	Median number of points according to INCAT lower extremity scale		up to 12 months
Secondary	Mean and median number of points according to combined clinical and electrophysiological score		up to 12 months
Secondary	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	Val30Met; Ile107Val; Phe33Leu; Ala81Val; Ser23Asn; Ala25Thr; Val32Ala; Thr40Asn; Gly47Ala; Glu54Gln; Tyr69Phe; Glu92Lys; Thr119Met; Other	up to 12 months
Secondary	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:	CIDP; Lumbar/sacral radiculopathy; Lumbar canal stenosis; Paraproteinaemic peripheral neuropathy; Chronic progressive sensory/sensorimotor axonal idiopathic PN; AL amyloidosis; Fibromyalgia; Other (specify);	up to 12 months
Secondary	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:	manifestations, including specifically: Orthostatic hypotension; Syncope; Gastrointestinal motility disorders - i. Constipation; ii. Early satiety; iii. Diarrhea; iv. Nausea, vomiting; Erectile dysfunction; Neurogenic bladder; Recurrent urinary infections; Anhidrosis;	up to 12 months
Secondary	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:	Left ventricular hypertrophy; Left bundle branch block; Atrioventricular block; Heart failure with preserved ejection fraction; Elevated serum N-terminal-proB-type natriuretic peptide (NT-proBNP) concentration; Cardiac valve stenosis; Cardiac valve regurgitation; Tachyarrhythmia; Other (specify); None;	up to 12 months
Secondary	proportion of patients taking specific groups of cardiovascular medications at the time of CTS surgery and at the time of prospective visit:	Angiotensin converting enzyme inhibitor (ACEI) (specify); Angiotensin receptor blocker (ARB) (specify); Angiotensin receptor and neprilysin inhibitor (ARNI); Sodium-glucose transporter type 2 inhibitor (SGLT2i) (specify); Mineralocorticoid receptor antagonist (MRA) (specify); Beta-blocker (specify); Diuretic (specify); Other cardiovascular (CV) medications (specify); Other (specify);	up to 12 months
Secondary	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	Vitreous body inclusions (opacification); Glaucoma; Abnormal conjunctival vessels; Papillary abnormalities; Dry eye; Other (specify);	up to 12 months
Secondary	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:	Spinal stenosis; Osteoarthritis, including hip and knee arthroplasty; Trigger finger; Charcot's joints; Biceps tendon rupture; Rotator cuff injury; Other (specify);	up to 12 months
Secondary	proportion of patients with concomitant renal dysfunction, including specifically	Elevated SCr level (based on the local laboratory reference range); Decreased eGFR (<60 ml/min/1.73m2); Presence of albuminuria (=30 mg/g creatinine (=30 mg/g of creatinine or =30 mg/24h); Presence of proteinuria (according to urinalysis results); Ultrasound signs of amyloid nephropathy;	up to 12 months
Secondary	proportion of patients with confirmed length-dependent peripheral sensory-motor neuropathy based on NCS results		up to 12 months
Secondary	proportion of patients with reduced peripheral sensory nerve conduction velocity at =1 site		up to 12 months
Secondary	proportion of patients with reduced motor sensory nerve conduction velocity at =1 site		up to 12 months
Secondary	proportion of patients with reduced/absent SAP amplitude at =1 site		up to 12 months
Secondary	proportion of patients with reduced/absent dCMAP amplitude at =1 site		up to 12 months
Secondary	proportion of patients with reduced/absent pCMAP amplitude at =1 site		up to 12 months
Secondary	proportion of patients in the specific categories of the modified Rankin scale	-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	up to 12 months