Discussion
heterogenous, worsening disability, loss of muscle mass, pain, muscle disease
DISEASE PROGRESSION, ADVERSE EVENTS, EVENT, DISEASE, MUSCLE DISEASE
In this 26-week pilot study comparing the combination of testosterone supplementation and exercise training versus exercise alone, we were unable to detect a significant additional effect of testosterone on muscle strength or physical function in men with IBM over the 12-week intervention period. However, individuals on testosterone had improved emotional wellbeing on the RAND-SF-36. Twelve men requested the OLE due to perceived positive effects of testosterone.The emotional wellbeing aspect of the RAND-SF-36 refers to general mental health including questions related to psychological distress and well-being. In this study, there was an improvement in emotional wellbeing when on testosterone, which suggests it may have a positive influence on mood. Other aspects of the RAND-SF-36 scale did not change significantly between the two treatment periods, meaning that individuals did not feel that testosterone helped with physical functioning, social functioning, pain, energy or role limitations due to emotional / physical health.The natural history of IBM is one of relentless decline with progressive loss of muscle mass, strength and worsening disability. Prior studies have shown an annual decline in the IBMFRS between 2.7–3.8 points per year [The most commonly reported adverse events during the trial were falls. Unfortunately, due to the nature of IBM, falls can be a particularly common event independent of age and years since first symptoms [In the post study survey given to participants and their partners, 70% of participants and 60% of their partners correctly determined when the participant was on the testosterone arm due to perceived changes in libido and energy. This has the potential to unintentionally unblind the study and bias the results, but also highlights an important area for discussion with patients receiving testosterone therapy. Increases in libido and energy and mood changes are likely to impact patients’ relationships and this may in turn affect the acceptability of testosterone as a therapy. Future studies need to consider and potentially allow for the impact of testosterone on these domains within the study design.Strengths of this study include the randomised study allocation and its double-blind crossover design. Many parameters were assessed to enable a more comprehensive analysis of the potential relationship between IBM and testosterone replacement therapy. Participant adherence was excellent throughout the crossover study with no participant drop out. Limitations include the small, heterogenous population of individuals with IBM. However this is a relatively large sample size for a single centre randomised trial given the prevalence of the disease within Australia and globally. Given that this is a relatively rare condition, individuals enrolled were at vastly different stages of disease progression. This posed a challenge in creation of homogenous exercise programmes and determining suitable outcome measures, as some individuals were wheelchair-bound or unable to participate in some physical assessments. The crossover trial design attempted to mitigate this issue, however a large multi-centre study would be better as it will allow for selection of a larger, more homogenous group of individuals with IBM with outcome measures better suited to their functional level. There is also the possibility that no significance was noted in this study because the 12-week duration of intervention was too short. Although 12 weeks should be sufficient in healthy populations to detect changes in the predetermined outcome measures adopted here, perhaps in an older population with muscle disease a longer duration study is required to be able to measure a significant difference. For trials in the future, it may be beneficial to perform a double blinded, randomised controlled trial over a longer duration (e.g. 6 to 12 months).In conclusion, this pilot study did not suggest a significant additive effect of testosterone combined with exercise over 12 weeks to improve muscle strength or physical function in men with IBM. However, testosterone improved patient perceived emotional wellbeing; and may confer a stabilisation effect on specific measures muscle strength and physical function. The complete retention rate of the main study and the willingness of most participating men to enter an OLE suggests that larger and longer duration studies using testosterone are warranted and feasible in this population.