Clinical Trial Results:
A Feasibility Study of Bezafibrate in Mitochondrial Myopathy
Summary


EudraCT number 
201500050824 
Trial protocol 
GB 
Global end of trial date 
23 Mar 2017

Results information


Results version number 
v1(current) 
This version publication date 
01 Nov 2018

First version publication date 
01 Nov 2018

Other versions 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
7406


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT02398201  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
Newcastle upon Tyne Hospitals NHS Foundation Trust


Sponsor organisation address 
Queen Victoria Road, Newcastle upon Tyne, United Kingdom, NE1 4LP


Public contact 
Patrick Chinnery, Newcastle University, +44 01912418611, patrick.chinnery@ncl.ac.uk


Scientific contact 
Patrick Chinnery, Newcastle University, +44 01912418611, patrick.chinnery@ncl.ac.uk


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
20 Mar 2018


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
23 Mar 2017


Global end of trial reached? 
Yes


Global end of trial date 
23 Mar 2017


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
To undertake a proof of concept study to determine whether bezafibrate can improve mitochondrial function in individuals with mitochondrial disease; to determine whether further study warranted in an RCT; and to have data to inform any power calculations for potential future studies.


Protection of trial subjects 
Two data monitoring committee meetings during the course of the study. The first of these discussed adverse events occurring within the study, and due to hypoglycaemic episodes, further monitoring of blood sugars was advised if participants were recruited to higher doses of bezafibrate. Substantial amendment submitted to reflect this.


Background therapy 
None  
Evidence for comparator 
No disease modifying treatments currently available.  
Actual start date of recruitment 
09 Nov 2015


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
United Kingdom: 6


Worldwide total number of subjects 
6


EEA total number of subjects 
6


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
0


Adolescents (1217 years) 
0


Adults (1864 years) 
6


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
Participants were provided with introductory information via i) routine clinic appointments; or ii) the UK mitochondrial disease cohort, inviting them to contact the study team. With further contact from participants, the participant information sheet was provided and questions answered via telephone before a screening visit was arranged.  
Preassignment


Screening details 
Screening was undertaken at the Clinical Research Facility, Royal Victoria Infirmary, Newcastle upon Tyne. 9 individuals were screened and 6 were recruited to the study.  
Period 1


Period 1 title 
Baseline


Is this the baseline period? 
Yes  
Allocation method 
Not applicable


Blinding used 
Not blinded  
Arms


Arm title

Group 1  
Arm description 
  
Arm type 
Experimental  
Investigational medicinal product name 
Bezafibrate


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
200mg TDS PO for 6/52 followed by 400mg TDS PO for 6/52




Period 2


Period 2 title 
Wk 6 Treatment


Is this the baseline period? 
No  
Allocation method 
Not applicable


Blinding used 
Not blinded  
Arms


Arm title

Group 1  
Arm description 
  
Arm type 
Experimental  
Investigational medicinal product name 
Bezafibrate


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
200mg TDS PO for 6/52 followed by 400mg TDS PO for 6/52




Period 3


Period 3 title 
Wk 12 End of Treatment


Is this the baseline period? 
No  
Allocation method 
Not applicable


Blinding used 
Not blinded  
Arms


Arm title

Group 1  
Arm description 
  
Arm type 
Experimental  
Investigational medicinal product name 
Bezafibrate


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
200mg TDS PO for 6/52 followed by 400mg TDS PO for 6/52





Baseline characteristics reporting groups


Reporting group title 
Baseline


Reporting group description 
  


Subject analysis sets


Subject analysis set title 
Group 1


Subject analysis set type 
Full analysis  
Subject analysis set description 
All recruited participants





End points reporting groups


Reporting group title 
Group 1


Reporting group description 
  
Reporting group title 
Group 1


Reporting group description 
  
Reporting group title 
Group 1


Reporting group description 
  
Subject analysis set title 
Group 1


Subject analysis set type 
Full analysis  
Subject analysis set description 
All recruited participants



End point title 
Change in Complex I Respiratory Chain Enzyme Activity between baseline & week 12  
End point description 

End point type 
Primary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
Change in CI between weeks 0 and 12.  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[1]}  
Pvalue 
= 0.7  
Method 
paired t test  
Confidence interval 

Notes [1]  exploratory 


End point title 
dChange in Complex II Respiratory Chain Enzyme Activity between baseline & week 12  
End point description 

End point type 
Primary


End point timeframe 
Measured at weeks 0 and 12




Statistical analysis title 
Change in CII activity between wks 0 and 12  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[2]}  
Pvalue 
= 0.02  
Method 
paired t test  
Confidence interval 

Notes [2]  exploratory 


End point title 
Change in Complex III Respiratory Chain Enzyme Activity between baseline & week 12I  
End point description 

End point type 
Primary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
Change in CIII activity between weeks 0 and 12  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[3]}  
Pvalue 
= 0.99  
Method 
paired t test  
Confidence interval 

Notes [3]  exploratory 


End point title 
Change in Complex IV Respiratory Chain Enzyme Activity between baseline & week 12  
End point description 

End point type 
Primary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
Change in CIV activity between weeks 0 and 12.  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[4]}  
Pvalue 
= 0.96  
Method 
paired t test  
Confidence interval 

Notes [4]  exploratory 


End point title 
Change in Citrate Synthase  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12




Statistical analysis title 
Change in CS activity between weeks 0 and 12  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[5]}  
Pvalue 
= 0.72  
Method 
paired t test  
Confidence interval 

Notes [5]  exploratory 


End point title 
Change in mitochondrial DNA copy number  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
change in mtDNA CN between weeks 0 and 12  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[6]}  
Pvalue 
= 0.64  
Method 
paired t test  
Confidence interval 

Notes [6]  exploratory 


End point title 
Change in serum FGF21  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12




Statistical analysis title 
Change in FGF21  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[7]}  
Pvalue 
= 0.021 ^{[8]}  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [7]  exploratory [8]  a priori threshold for significance = <0.05 GreenhouseGeisser correction Two sided 


End point title 
Change in serum GDF15  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in GDF15  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[9]}  
Pvalue 
= 0.007 ^{[10]}  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [9]  exploratory [10]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in muscle PGC1alpha level  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0 and 12 weeks




Statistical analysis title 
Change in PGC1alpha level  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[11]}  
Pvalue 
= 0.63  
Method 
paired t test  
Confidence interval 

Notes [11]  exploratory 


End point title 
Change in τ 1/2 PCr between 0 and 12 weeks  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
Change in Ï„ 1/2 PCr between wks 0 & 12  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
12


Analysis specification 
Prespecified


Analysis type 
other ^{[12]}  
Pvalue 
= 0.345 ^{[13]}  
Method 
paired t test  
Confidence interval 

Notes [12]  exploratory [13]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in Myocardial PCr/ATP ratio  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12




Notes [14]  n=5 participants scanned at baseline due to technical error. 4 individuals had paired samples. 

Statistical analysis title 
Change in myocardial PCr/ATP ratio  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
8


Analysis specification 
Prespecified


Analysis type 
other ^{[15]}  
Pvalue 
= 0.035  
Method 
paired t test  
Confidence interval 

Notes [15]  exploratory 


End point title 
Change in Peak cardiac left ventricular torsion  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
Change in mean left ventricular torsion  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
other ^{[16]}  
Pvalue 
= 0.8 ^{[17]}  
Method 
paired t test  
Confidence interval 

Notes [16]  exploratory [17]  a priori threshold for significance = <0.05 Two sided 


End point title 
change in mean peak VO2  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




Statistical analysis title 
Change in peak VO2  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
^{[18]}  
Pvalue 
= 0.91 ^{[19]}  
Method 
paired t test  
Confidence interval 

Notes [18]  exploratory [19]  a priori threshold for significance = <0.05 Two sided 


End point title 
change in peak power  
End point description 

End point type 
Secondary


End point timeframe 
measured at weeks 0 and 12.




Statistical analysis title 
Change in mean peak power (W)  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
other ^{[20]}  
Pvalue 
= 0.87 ^{[21]}  
Method 
paired t test  
Confidence interval 

Notes [20]  exploratory [21]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in arteriovenous oxygen differential 012wks  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12




Statistical analysis title 
Change in mean peak aVO2 diff  
Comparison groups 
Group 1 v Group 1


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
^{[22]}  
Pvalue 
= 0.37 ^{[23]}  
Method 
paired t test  
Confidence interval 

Notes [22]  exploratory [23]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in NMDAS Total  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6 and 12 weeks




Statistical analysis title 
Change in NMDAS_total  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.115 ^{[24]}  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [24]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in NMQ  mobility  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0,6 and 12 weeks




Statistical analysis title 
change in NMQ  mobility  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[25]}  
Pvalue 
= 0.127  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [25]  exploratory 


End point title 
Change in NMQ  ADLs  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0,6 and 12 weeks




Statistical analysis title 
Change in NMQ  ADLs  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[26]}  
Pvalue 
= 0.062  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [26]  exploratory 


End point title 
Change in NMQ  Energy  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6, 12 weeks




Statistical analysis title 
Change in NMQ  Energy  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[27]}  
Pvalue 
= 0.127  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [27]  exploratory 


End point title 
Change in NMQ  Vision  
End point description 

End point type 
Secondary


End point timeframe 
measured at Wk 0, 6 and 12 weeks




Statistical analysis title 
Change in NMQ _ Vision  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[28]}  
Pvalue 
= 0.425  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [28]  exploratory 


End point title 
Change in NMQ  Communication  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in NMQ  Communication  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[29]}  
Pvalue 
= 0.746  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [29]  exploratory 


End point title 
Change in NMQ  Memory  
End point description 

End point type 
Secondary


End point timeframe 
measured at 0,6 and 12 weeks




Statistical analysis title 
Change in NMQ  Memory  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[30]}  
Pvalue 
= 0.08  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [30]  exploratory 


End point title 
Change in NMQ  Food  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6 and 12 weeks




Statistical analysis title 
change in NMQ _food  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[31]}  
Pvalue 
= 0.094  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [31]  exploratory 


End point title 
Change in NMQ  Pain  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6, 12 weeks




Statistical analysis title 
change in NMQ  Pain  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[32]}  
Pvalue 
= 0.514  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [32]  exploratory 


End point title 
Change in NMQ  Muscle  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in NMQ  Muscle  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[33]}  
Pvalue 
= 0.235  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [33]  exploratory 


End point title 
Change in NMQ  Migraine  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
change in NMQ  Migraine  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[34]}  
Pvalue 
= 0.471  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [34]  exploratory 


End point title 
Change in NMQ  Emotions  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
change in NMQ  Emotions  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[35]}  
Pvalue 
= 0.173  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [35]  exploratory 


End point title 
Change in NMQ  Stigma  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in NMQ  Stigma  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[36]}  
Pvalue 
= 0.47  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [36]  exploratory 


End point title 
Change in NMQ  Family Role  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in NMQ  Family role  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[37]}  
Pvalue 
= 0.546  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [37]  exploratory 


End point title 
Change in NMQ  Personal Relations  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in NMQ  Personal Relations  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[38]}  
Pvalue 
= 0.277  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [38]  exploratory 


End point title 
Change in NMQ  Social Role  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in NMQ  social role  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[39]}  
Pvalue 
= 0.258  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [39]  exploratory 


End point title 
Change in Physical Component Score  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in Physical Component Score  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[40]}  
Pvalue 
= 0.663  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [40]  exploratory 


End point title 
Change in Mental Component Score  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in Mental Component Score  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[41]}  
Pvalue 
= 0.028  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [41]  exploratory 


End point title 
Change in Fatigue Impact Score_Total  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6 and 12 weeks.




Statistical analysis title 
Change in FIS  Total  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[42]}  
Pvalue 
= 0.252  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [42]  exploratory 


End point title 
Change in Fatigue Impact Score_Physical  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6 and 12 weeks.




Statistical analysis title 
Change in FIS  Physical  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[43]}  
Pvalue 
= 0.127  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [43]  exploratory 


End point title 
Change in Fatigue Impact Score_Cognitive  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6 and 12 weeks.




Statistical analysis title 
Change in FIS  Cognitive  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[44]}  
Pvalue 
= 0.289  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [44]  exploratory 


End point title 
Change in Fatigue Impact Score_Social  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 , 6 and 12.




Statistical analysis title 
Change in FIS  Social  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[45]}  
Pvalue 
= 0.602  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [45]  exploratory 


End point title 
Change in IPAQ Score  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in IPAQ score  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[46]}  
Pvalue 
= 0.084 ^{[47]}  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [46]  exploratory [47]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in Daytime Acceleration  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 , 6 and 12.




Statistical analysis title 
Change in daytime acceleration  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
other ^{[48]}  
Pvalue 
= 0.074 ^{[49]}  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [48]  exploratory [49]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in Vigorous Activity  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in vigorous activity  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
other ^{[50]}  
Pvalue 
= 0.021 ^{[51]}  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [50]  exploratory [51]  a priori threshold for significance = <0.05 Two sided 


End point title 
Change in Moderate Activity  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in time in moderate activity  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
other ^{[52]}  
Pvalue 
= 0.165  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [52]  exploratory 


End point title 
Change in Light Activity  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0, 6 and 12.




Statistical analysis title 
Change in time in light activity  
Comparison groups 
Group 1 v Group 1 v Group 1


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
other ^{[53]}  
Pvalue 
= 0.041  
Method 
Repeated measures ANOVA  
Confidence interval 

Notes [53]  exploratory 


End point title 
Change in Muscle heteroplasmy  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




No statistical analyses for this end point 


End point title 
Change in Urine Heteroplasmy  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




No statistical analyses for this end point 


End point title 
Change in Blood Heteroplasmy  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




No statistical analyses for this end point 


End point title 
Change in COX deficient Fibres  
End point description 

End point type 
Secondary


End point timeframe 
Measured at weeks 0 and 12.




No statistical analyses for this end point 


End point title 
Change in Timed Up and Go  
End point description 

End point type 
Secondary


End point timeframe 
Measured at 0, 6 and 12 weeks.




No statistical analyses for this end point 


Adverse events information


Timeframe for reporting adverse events 
Enrolment in study up to 2 weeks after taking final dose of IMP.


Adverse event reporting additional description 
Given the multisystemic feature of mitochondrial disorders, and the low numbers of participants, all adverse events were captured during the study period.


Assessment type 
Nonsystematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
20


Reporting groups


Reporting group title 
Group 1


Reporting group description 
All participants recruited to study, who it was anticipated at onset would take 6 weeks bezafibrate at 200mg TDS; followed by 400mg TDS for 6 weeks.  


Frequency threshold for reporting nonserious adverse events: 0%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

05 Jun 2015 
MHRA approval for use of protocol V2.0 obtained 11 June 2015.
REC Approval for protocol V2.0 24 July 2015.
Protocol updated from V1.0 to reflect changes in eligibility criteria to make sure the study was relevant to the patient population. MHRA only approved V2.0 protocol. Amendment submitted to ensure REC approval in place for V2.0 protocol also. 

09 Dec 2015 
REC approval for addition of Prof Horvath as PI; increased time between screen and baseline; change in accelerometry equipment; addition of statin washout; removal of site specific muscle biopsy details; clarification that potential biomarkers will be analysed in muscle tissue and serum; streamlining information within the protocol. 

19 Apr 2016 
Updated following Trial Oversight Committee meeting, to improve blood glucose monitoring for participants in light of hypoglycaemic episodes. 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
Adverse event profile in the first six participants, and in particular hypoglycaemic episodes, led to discontinuation of study after 6 individuals. It was not thought that persons would tolerate a higher dose. 