Clinical Trial: A Study of Bezafibrate in Mitochondrial Myopathy

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Feasibility Study of Bezafibrate in Mitochondrial Myopathy

Brief Summary:

The purpose of this study is to gather preliminary data on whether bezafibrate can improve cellular energy production in mitochondrial disease.

Mitochondrial diseases are rare inherited disorders that arise due to deficient energy production within the cells of the body. Consequently, the typical clinical features arise in organs with high energy requirements. Mitochondrial disorders exhibit highly variable clinical effects, both between individuals and within families. Characteristic symptoms include muscle weakness (myopathy), hearing loss, migraine, epilepsy and stroke like episodes in addition to diabetes and heart problems. Mitochondrial disorders can therefore impact considerably on both quality of life and life expectancy. Despite this, no proven disease modifying treatments are available.

Pre-clinical studies have identified that several existing medications improve mitochondrial function. Of these, bezafibrate has the best supportive data and, because it is already licensed as a treatment for high blood fats, has a well characterised side effect profile.

The investigators will therefore conduct a feasibility study of bezafibrate in people with mitochondrial myopathy. Ten affected participants will be recruited and will receive a titrating course of bezafibrate three times daily for 12 weeks.


Detailed Summary:

Mitochondrial disorders are genetically determined metabolic diseases affecting approximately 1 in 5000 people. Current strategies for treating mitochondrial disorders are limited, and restricted to alleviating symptoms. A recently published Cochrane review did not identify any disease modifying treatments of proven benefit. There is therefore an urgent and currently unmet need for treatments that modify the underlying biochemical deficit and disease trajectory.

Improving deficient oxidative phosphorylation (OXPHOS) pathways through induction of mitochondrial biogenesis is a potential approach to the treatment of mitochondrial disorders. This involves stimulating transcription factors for both nuclear and mitochondrial genomes simultaneously in order to up-regulate respiratory chain (RC) gene expression. This role is fulfilled by peroxisome proliferator activated receptor (PPAR)-γ coactivator-1α (PGC-1α); a pivotal transcriptional co-factor widely considered the master regulator of mitochondrial biogenesis.

PGC-1α interacts with a number of transcription factors. These include α, β/δ and γ isoforms of the peroxisomal proliferator activated receptors (PPARs). This group of ubiquitously expressed nuclear receptors is activated by binding of fatty acids. Subsequently, transcription of genes involved in mitochondrial fatty acid oxidation is induced, thereby enabling cellular metabolic shift from glycolysis. Additionally, PGC-1α co-activates estrogen related receptor alpha (ERRα); nuclear respiratory factors (NRF) 1 and 2 (transcription factors bound to promoter regions of target nuclear genes involved in the respiratory chain); and TFAM (transcription factor A mitochondrial), which modulates mitochondrial DNA transcription and replication.

Same as current

Current Secondary Outcome:

  • Change in citrate synthase [ Time Frame: baseline and 12 weeks ]
  • Change in mitochondrial DNA copy number [ Time Frame: baseline and 12 weeks ]
  • Change in COX negative fibres [ Time Frame: baseline and 12 weeks ]
  • Change in serum Fibroblast Growth Factor-21 concentration [ Time Frame: baseline, 3, 6, 9, 12 weeks ]
  • Change in PGC-1alpha concentration [ Time Frame: baseline, 3, 6, 9, 12 weeks ]
  • Change in micro-RNA expression pattern [ Time Frame: baseline, 3, 6, 9, 12 weeks ]
  • Change in cardiac 31P-MRS [ Time Frame: baseline and 12 weeks ]
    We will specifically analyse ATP production and muscle phosphocreatine pre and post bezafibrate
  • Change in cardiac cine MRI [ Time Frame: baseline and 12 weeks ]
    We will analyse LV (left ventricular) torsion pre and post bezafibrate
  • Change in skeletal muscle 31P-MRS [ Time Frame: baseline and 12 weeks ]
    We will analyse ATP production, muscle phosphocreatine, t1/2 PCR (phosphocreatine), muscle lipid content and volume.
  • Change in IPAQ (international physical activity questionnaire) score [ Time Frame: baseline, 6 and 12 weeks ]
  • Change in accelerometry [ Time Frame: baseline, 6 and 12 weeks ]
  • Change in Timed Up and Go (TUG) time [ Time Frame: baseline, 6 and 12 weeks ]
  • Change in NMDAS (Newcastle Mitochondrial Disease Adult Scale) score [ Time Frame: baseline, 6 and 12 weeks ]
  • Change in heteroplasmy level [ Time Frame: baseline and 12 weeks ]
    measured in blood, urine and muscle
  • Change in NMQ (Newcastle Mitochondrial Disease Quality of Life) Score [ Time Frame: baseline, 6 and 12 weeks ]
  • Change in Fatigue Impact Scale score [ Time Frame: baseline, 6 and 12 weeks ]
  • Number of Adverse Events [ Time Frame: 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14 weeks ]
    Adverse events will be captured every week with opportunistic capture between visits as required.
  • Change in Full Blood Count [ Time Frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 weeks ]
    White cell count; Haemoglobin; Platelet count
  • Change in Urea & Electrolytes [ Time Frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 weeks ]
    Sodium; Potassium; Urea; Creatinine;
  • Change in Liver Function Tests [ Time Frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 weeks ]
    Alkaline Phosphatase, Alanine Transferase, Aspartate Aminotransferase, Gamma Glutamyl Transferase
  • Change in Creatine Kinase [ Time Frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 weeks ]
  • Change in Prothrombin Time [ Time Frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 weeks ]


Original Secondary Outcome: Same as current

Information By: Newcastle-upon-Tyne Hospitals NHS Trust

Dates:
Date Received: March 9, 2015
Date Started: September 2015
Date Completion: August 2017
Last Updated: March 29, 2017
Last Verified: March 2017