Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

Official title:

Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01847716
• Other study ID #: 13IC0457
• Status: Terminated
• Start date: October 2013
• Est. completion date: August 2016

Study information

• Verified date: September 2018
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 33
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Muscle Weakness
• Paresis
• Pulmonary Arterial Hypertension

Locations

Country	Name	City	State
United Kingdom	Royal Brompton Hospital	London

Sponsors (3)

Lead Sponsor	Collaborator
Imperial College London	Medical Research Council, Royal Brompton & Harefield NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma growth and differentiation factor 15 levels in participants with and without muscle wasting	Muscle wasting will be defined by quadriceps cross sectional area measured by ultrasound	30 months
Secondary	Correlation of plasma Growth and differentiation factor 15 levels with muscle strength	Muscle strength will be measured by quadriceps maximal volitional capacity percent predicted	30 months
Secondary	Change in fibre type in muscle biopsy		30 months
Secondary	GDF-15 levels in biopsy specimens		30 months
Secondary	Correlation of plasma Growth and differentiation factor 15 levels with brain natriuretic protein levels		30 months
Secondary	Correlation of plasma Growth and differentiation factor 15 levels with fat free mass index	Fat free mass index will be measured by bioelectrical impedence	30 months
Secondary	Correlation of plasma Growth and differentiation factor 15 levels with quality of life	Quality of life will be measured by St. George's respiratory questionnaire	30 months
Secondary	Correlation of plasma Growth and differentiation factor 15 levels with exercise tolerance	Exercise tolerance will be measured by six minute walk test	30 months
Secondary	Correlation of plasma Growth and differentiation factor levels 15 with physical activity levels	Physical activity will be measured by Sensewear armband	30 months
Secondary	Correlation of plasma Growth and differentiation factor levels 15 with echocardiographic measures of severity of pulmonary hypertension		30 months
Secondary	Correlation of GDF-15 levels in biopsy specimens with muscle wasting and weakness	Wasting will be measured by quadriceps cross sectional area and weakness will be defined by quadriceps maximal volitional capacity	30 months
Secondary	Determine the contribution of atrophy and autophagy to muscle wasting in PAH	Muscle biopsy specimens will be evaluated using microscopy and real time polymerase chain reaction	30 months
Secondary	Determine the contribution of SMAD and non-SMAD signalling pathways to the development of muscle weakness and wasting in PAH	Phosphorylation of SMAD and non-SMAD signalling will be determined by western blot	30 months