Clinical trial NCT01847716: Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension
Official title: Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Muscle Weakness
Pulmonary Arterial Hypertension
Keywords: Muscle weakness
Pulmonary arterial hypertension
Transforming growth factor beta
Growth and differentiation factor 15
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: Royal Brompton & Harefield NHS Foundation Trust
First posted: 2013-05-07
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Clinics at Royal Brompton and Hammersmith hospital

Brief summary: Pulmonary arterial hypertension (PAH) is a disease that causes raised blood pressure in blood vessels that pick up oxygen from the lungs. It has a life expectancy similar to some cancers. There is treatment available but there is no cure. We now know that PAH is associated with weakness in the muscles in the legs, which contributes to the symptoms patients' experience. Researchers believe that certain proteins found in high levels in the blood of patients with other chronic diseases can affect muscle function and growth. One of these proteins is called growth differentiating factor (GDF) 8, high levels of which are associated with muscle weakness in chronic obstructive pulmonary disease(COPD) and heart failure (HF). Interestingly there are drugs available which block the actions of GDF-8 on muscle cells which has been shown in animals to result in increased muscle size. A related protein called GDF-15 is found in elevated levels in patients PAH, and is linked to prognosis. Our preliminary data suggests that GDF-15 can also directly influence muscle size in a number of situations. We aim to investigate the role of GDF-15 and related molecules in the development of muscle weakness in patients with PAH. We will do this by measuring certain markers of muscle weakness and taking blood and muscle samples in patients and controls. We will then compare the levels of GDF-15 in these tissues in those with and without muscle wasting. We hope this work will lead to a greater understanding of the role of GDF-15 in the development of muscle weakness in patients with PAH. GDF-15 levels may be important in allowing us to define which patients have muscle weakness. In the future we aim to perform a clinical trial of drugs which block the actions of GDF-15.


Eligibility criteria: Inclusion Criteria:

* Patients with pulmonary arterial hypertension with New York Heart Association stage II - III disease will be eligible for recruitment in the patient portion of the trial. Interested healthy age matched volunteers will also be recruited.

Exclusion Criteria:

* Patients and volunteers will be excluded if they have significant co-morbidities including other cardiorespiratory disease, metabolic abnormalities including diabetes or thyroid disorders. They will be excluded if they cannot safely exercise and perform a six minute walk test or if they are wheelchair bound.

Primary outcomes:
measure: Plasma growth and differentiation factor 15 levels in participants with and without muscle wasting
timeFrame: 30 months
Secondary outcomes:
measure: Correlation of plasma Growth and differentiation factor 15 levels with muscle strength
timeFrame: 30 months
measure: Change in fibre type in muscle biopsy
timeFrame: 30 months
measure: GDF-15 levels in biopsy specimens
timeFrame: 30 months
measure: Correlation of plasma Growth and differentiation factor 15 levels with brain natriuretic protein levels
timeFrame: 30 months
measure: Correlation of plasma Growth and differentiation factor 15 levels with fat free mass index
timeFrame: 30 months
measure: Correlation of plasma Growth and differentiation factor 15 levels with quality of life
timeFrame: 30 months
measure: Correlation of plasma Growth and differentiation factor 15 levels with exercise tolerance
timeFrame: 30 months
measure: Correlation of plasma Growth and differentiation factor levels 15 with physical activity levels
timeFrame: 30 months
measure: Correlation of plasma Growth and differentiation factor levels 15 with echocardiographic measures of severity of pulmonary hypertension
timeFrame: 30 months
measure: Correlation of GDF-15 levels in biopsy specimens with muscle wasting and weakness
timeFrame: 30 months
measure: Determine the contribution of atrophy and autophagy to muscle wasting in PAH
timeFrame: 30 months
measure: Determine the contribution of SMAD and non-SMAD signalling pathways to the development of muscle weakness and wasting in PAH
timeFrame: 30 months
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
affiliation: Imperial College / Royal Brompton Hospital
name: Stephen J Wort, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Garfield BE, Crosby A, Shao D, Yang P, Read C, Sawiak S, Moore S, Parfitt L, Harries C, Rice M, Paul R, Ormiston ML, Morrell NW, Polkey MI, Wort SJ, Kemp PR. Growth/differentiation factor 15 causes TGFbeta-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension. Thorax. 2019 Feb;74(2):164-176. doi: 10.1136/thoraxjnl-2017-211440. Epub 2018 Dec 15.