Metabolic Myopathy in Endocrinopathy

NCT05456997 | Terminated

• 1 other identifier: Pending
• Study Type: observational
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

Endocrine diseases including Cushing's syndrome and phaeochromocytoma/paraganglioma (PPGL) but not Conn's syndrome are associated with muscle wasting and weakness. The study's aim is to identify epigenetic determinants of muscle homeostasis in these conditions following medical treatment and adrenalectomy. This is an observational pilot study that will recruit 66 patients from 3 diagnostic groups: Cushing's syndrome (16), PPGL (20) and Conn's syndrome (30). Indices of muscle bulk and strength will be assessed at diagnosis and at outpatient follow-up 6-9 weeks after adrenalectomy. At these times blood and urine will be collected and a muscle biopsy taken from the operation site at the time of surgery. Pathway analysis in these samples will identify potentially novel signalling pathways contributing to muscle wasting via prolonged exposure to high levels of corticosteroid and catecholamines. This will highlight commonalities and differences in pathogenesis of muscle wasting from a variety of different causes. Finally, it will inform identification of novel therapies for muscle atrophy.

Conditions

Cushing Syndrome; Pheochromocytoma; Conns Syndrome; Metabolic Myopathy

Keywords

Epigenetic control

Outcome Measures

Primary Outcomes (7)

• Change in cross sectional area of the Rectus Femoris (RFcsa)

  RFcsa will be calculated using B-mode ultrasound (US) at pre-determined time points

  Day 0/ at presentation to 6-9 week follow up.

• Change in Hand Held Dynamometry strength (grip strength)

  Hand-held dynamometry will be assessed in both hands (the maximum of 3 attempts)

  Day 0/ at presentation to 6-9 week follow up.

• Change in Knee straightening dynamometry

  The test will be conducted using a Lafayette Manual Muscle Tester. Joint knee moment (torque) and strength will be measured.

  Day 0/ at presentation to 6-9 week follow up.

• Change in Short Physical Performance Battery (SPPB)

  SPPB is a measure of patients' functional status: scores range from 0 (worst performance) to 12 (best performance).

  Day 0/ at presentation to 6-9 week follow up.

• Change in Lying and Standing Vital Capacity (FVC - forced vital capacity) ratio

  Lying and standing vital capacity will be measured using a hand held spirometer

  Day 0/ at presentation to 6-9 week follow up.

• Change in bio-impedance indices of body composition

  Indices of body composition will be measured by electrical impedance.

  Day 0/ at presentation to 6-9 week follow up.

• Change in rectus femoris pixel intensity

  Pixel intensity is a measure of muscle quality measured by B mode ultrasound

  Day 0/ at presentation to 6-9 week follow up.

Secondary Outcomes (10)

• Changes in plasma markers of muscle homeostasis by enzyme-linked immunosorbent assay (ELISA)

  Day 0/ at presentation & 6-9 week follow up.

• Changes in plasma markers of muscle homeostasis by enzyme-linked immunosorbent assay (ELISA)

  Day 0/ at presentation & 6-9 week follow up.

• Changes in plasma markers of muscle homeostasis by enzyme-linked immunosorbent assay (ELISA)

  Day 0/ at presentation & 6-9 week follow up.

• Changes in steroid metabolism by mass spectroscopy in blood and urine

  Day 0/ at presentation to 6-9 week follow up.

• Assay in abdominal muscle of markers of muscle atrophy by western blot

  Intra-operatively during adrenalectomy

Study Arms (3)

Cushings syndrome

Patients with Cushing's syndrome treated medically prior to adrenalectomy

Procedure: Muscle biopsy

Phaeochromocytoma and paraganglioma (PPGL)

Patients with PPGL treated medically prior to adrenalectomy

Procedure: Muscle biopsy

Conn's syndrome

Patients with Conn's syndrome treated medically prior to adrenalectomy

Procedure: Muscle biopsy

Interventions

Muscle biopsy PROCEDURE

Patients will have muscle biopsies taken at time of surgery under general anaesthetic. Open biopsies from the operation field (abdominal wall) will be taken by the surgical team without extending or making new skin incisions. Briefly, muscle samples (approximately 0.5cm3) are excised and haemostasis secured. The muscle biopsies will be snap frozen and stored at -80°C for the analysis of pathways relevant to muscle homeostasis using biochemical and molecular techniques.

Conn's syndrome; Cushings syndrome; Phaeochromocytoma and paraganglioma (PPGL)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Inclusion criteria include any consenting adult receiving adrenalectomy surgery for Cushing's or Conn's syndrome or phaeochromocytoma/ paraganglioma (PPGL) at St Bartholomew's Hospital with no evidence of pre-hospital neuromuscular conditions.

You may qualify if:

• Above the age of 18
• Receiving both medical management and adrenalectomy for treatment of Cushing's syndrome or phaeochromocytoma at St Bartholomew's Hospital (SBH)

You may not qualify if:

• Previous Stroke
• Neuromuscular disease
• Disseminated Malignancy
• Underlying neuromuscular disease
• Paediatrics
• Non-consenting adults

Sponsors & Collaborators

• Barts & The London NHS Trust: lead
• Imperial College London: collaborator
• Queen Mary University of London: collaborator

Study Sites (1)

Barts Heart Centre

London, County (optional), EC1A 7BE, United Kingdom

Location

Related Publications (7)

• Bloch SA, Donaldson AV, Lewis A, Banya WA, Polkey MI, Griffiths MJ, Kemp PR. MiR-181a: a potential biomarker of acute muscle wasting following elective high-risk cardiothoracic surgery. Crit Care. 2015 Apr 7;19(1):147. doi: 10.1186/s13054-015-0853-5.

  PMID: 25888214 BACKGROUND

• Kemp PR, Griffiths M, Polkey MI. Muscle wasting in the presence of disease, why is it so variable? Biol Rev Camb Philos Soc. 2019 Jun;94(3):1038-1055. doi: 10.1111/brv.12489. Epub 2018 Dec 26.

  PMID: 30588725 BACKGROUND

• Donaldson A, Natanek SA, Lewis A, Man WD, Hopkinson NS, Polkey MI, Kemp PR. Increased skeletal muscle-specific microRNA in the blood of patients with COPD. Thorax. 2013 Dec;68(12):1140-9. doi: 10.1136/thoraxjnl-2012-203129. Epub 2013 Jun 28.

  PMID: 23814167 BACKGROUND

• Connolly M, Paul R, Farre-Garros R, Natanek SA, Bloch S, Lee J, Lorenzo JP, Patel H, Cooper C, Sayer AA, Wort SJ, Griffiths M, Polkey MI, Kemp PR. miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wasting. J Cachexia Sarcopenia Muscle. 2018 Apr;9(2):400-416. doi: 10.1002/jcsm.12266. Epub 2017 Dec 7.

  PMID: 29215200 BACKGROUND

• Kemp PR, Paul R, Hinken AC, Neil D, Russell A, Griffiths MJ. Metabolic profiling shows pre-existing mitochondrial dysfunction contributes to muscle loss in a model of ICU-acquired weakness. J Cachexia Sarcopenia Muscle. 2020 Oct;11(5):1321-1335. doi: 10.1002/jcsm.12597. Epub 2020 Jul 16.

  PMID: 32677363 BACKGROUND

• Garros RF, Paul R, Connolly M, Lewis A, Garfield BE, Natanek SA, Bloch S, Mouly V, Griffiths MJ, Polkey MI, Kemp PR. MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-acquired Weakness. Am J Respir Crit Care Med. 2017 Dec 1;196(11):1422-1433. doi: 10.1164/rccm.201701-0101OC.

  PMID: 28809518 BACKGROUND

• Ferrau F, Korbonits M. Metabolic comorbidities in Cushing's syndrome. Eur J Endocrinol. 2015 Oct;173(4):M133-57. doi: 10.1530/EJE-15-0354. Epub 2015 Jun 9.

  PMID: 26060052 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Abdominal wall muscle biopsy Blood and urine

MeSH Terms

Conditions

Cushing Syndrome; Pheochromocytoma; Hyperaldosteronism

Condition Hierarchy (Ancestors)

Adrenocortical Hyperfunction; Adrenal Gland Diseases; Endocrine System Diseases; Paraganglioma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Study Officials

• Mark J Griffiths, MB BS

  Bartshealth NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 4, 2022
• First Posted: July 13, 2022
• Study Start: March 20, 2023
• Primary Completion: September 30, 2023
• Study Completion: September 30, 2023
• Last Updated: October 16, 2023

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)