In this review we summarise the difficulties of conducting clinical trials in a slowly progressive disease such as CMT1A and the requirement for sensitive, reproducible and clinically relevant outcome measures.
We summarise the current array of CMT specific outcome measures subdivided into clinical outcome measures, functional outcome measures, patient reported outcome measures, biomarkers of disease burden and treatment specific biomarkers of target engagement. Although there is now an array of CMT specific outcome measures, which collectively incorporate clinically relevant, sensitive and reproducible outputs, a single outcome measure incorporating all three qualities remains elusive.
Since the discovery of the 17p duplication as the cause of CMT1A there has been significant progress made in both gene discovery for other forms of CMT and the development of therapies in pre-clinical models of CMT.
Furthermore, the evolving importance of the unfolded protein response UPR and macrophage associated inflammation in several forms of CMT1 has led to the development of small molecule inhibitors of the UPR and inflammatory response which have shown promise in animal models of the disease Das et al. The CMT field is therefore at a critical juncture where several promising therapies are ready to proceed to clinical trial, an essential step to be able to prove that a treatment does or does not work.
Poor trial design, including the use of insensitive clinical outcome measures, will fail to answer this question. An effective drug may show no efficacy in a clinical trial with too short a duration and an insensitive outcome measure. Similarly, multiple trials with inaccurate outcome measures may eventually result in a spuriously positive result.
This review will highlight some of the challenges of preparing for clinical trials in CMT and provide an update on the work that has been conducted to date. In the case of rare CMT subtypes, there may be too few patients globally to power such a trial, in which case a cross over trial design in which each patient serves as their own control may be necessary.
Following the publication of a single study reporting improvement of the C22 mouse model of CMT1A with ascorbic acid Passage et al. These were the first large, multicentre clinical trials in CMT and were all negative for the primary outcome measure.
Unfortunately, despite the considerable time and cost invested in these trials, it remains unanswered as to whether ascorbic acid is beneficial or not, as in hindsight, these trials were not powered to detect a meaningful response. For example, in two of the largest clinical trials, the primary outcome measure, the CMTNSv1, did not show any change in the placebo or ascorbic acid treated patients over the two-year duration of the trial Lewis et al.
Although an improvement with treatment in CMT1A is theoretically possible, by adulthood, most patients with CMT1A will have a degree of permanent axonal loss and so a more realistic aim of treatment would be to prevent or delay disease progression.
In order to optimise future trial design, the necessity to identify novel and more sensitive outcome measures able to detect disease progression over the normal two-year duration of a trial was recognised as critical. In addition, an international collaborative effort was made to collect prospective natural history data on the many subtypes of CMT to facilitate future trial design.
Due to the limited regenerative capacity of diseased peripheral nerves, the main aim of treatment in CMT is to prevent disease progression. It is therefore essential to have information on the rate of progression of a disease in order to understand what the expected effect size will be and ensure the trial is sufficiently powered in terms of subject recruitment.
For example, in spinal muscular atrophy type 1, in which infants born with the disease die within several months of birth, the rate of progression is so rapid that only a small number of patients and trial duration are required to detect a clinically meaningful response. Quality of life studies have highlighted the need to develop therapies for both the rapidly and slowly progressive forms of CMT. More than 6, patients have been enrolled into the study, with annual assessments of disease severity as measured by the CMT examination score dating back up to nine years Fridman et al.
Although this is an open label prospective study, the data will provide information on the required duration of any future trial and the likely number of subjects required.
This represents an important resource for quality of life and patient reported outcome measure development and for future trial recruitment, particularly for rare forms of CMT that may affect less than one hundred patients globally.
A good clinical outcome measure should have several properties; it should be sensitive to change, reproducible little variation in the accuracy of the measurement and clinically relevant.
The latter point is hard to define but is essential when designing a primary outcome measure for a trial. Outcome measures in Charcot-Marie-Tooth disease can be divided into one of five categories Table 1 ;. Clinical outcome measures that incorporate a clinical assessment by a health professional. Functional outcome measures in which the patient performs a series of tasks that assess their level of function. A summary of some of the currently available outcome measures for clinical trials in CMT.
We will now discuss advances in outcome measures for CMT for each of these five categories. The Charcot-Marie-Tooth neuropathy score version 1 was the first clinical outcome measures designed specifically for CMT and was modified from the total neuropathy score to measure impairment and progression in length dependent neuropathies Cornblath et al. More recently the CMTNSv2 has been re-evaluated in line with modern psychometrics such as item response theory.
The Rasch analysis of the second version showed a clumping of impairments amongst patients with moderate severity Sadjadi et al. This would suggest that the second version was insensitive for detecting small changes in progression between mild and moderate states or moderate and severe but was able to distinguish between mild and severely impaired patients.
The score was therefore modified by applying differing weights to the various elements. The sensitivity of the Rasch modified version of the CMTNSv2 to detect change over time has recently been assessed as part of the INC natural history study, demonstrating a small but significant disease progression detectable over two years Fridman et al.
The ONLS was employed as a secondary outcome measure in several of the initial ascorbic acid in CMT1 trials and was shown to be insensitive to change over the duration of the trial. A functional outcome measure is similar to a clinical outcome measure, but instead of a patient being examined by a health professional, the patient is asked to perform a number of tasks that assess specific functions and are scored independently.
Monitoring disease progression in childhood presents particular difficulties due to the inherent changes in an outcome measure as the child grows and develops. This is much less of a problem in adulthood where outcome measures stay relatively constant in control populations. A functional outcome measure in which a child performs a task has advantages over a regimented clinical outcome measure such as the CMTNSv2 where compliance with the clinical examination may be difficult Murphy et al. The CMT paediatric scale CMTPeds is an 11 item scale that measures seven functional domains including strength, dexterity, sensation, gait, balance, power and endurance producing a score of between 0 and The scale has been validated in large cohorts of children with CMT and age-specific normal scores calculated.
Rasch analysis of the scale has shown it to be a good overall model fit with no evidence of clustering. Furthermore, there is now longitudinal data from the INC demonstrating the sensitivity of the CMTPeds for detecting disease progression in children. The score was able to detect progression of 1. It was also able to detect progression of 2. This assumes no drop out and a treatment that can completely arrest the progression of the disease.
It utilises a number of outcome measures including hand grip, ankle-foot dorsiflexion and plantarflexion strength, nine-hole peg test to assess functional dexterity, balance beam, timed walk, stair climb and a timed up and go. Its future use in clinical trials depends on the outcome of active longitudinal studies examining the psychometric properties of the score and its responsiveness to change.
A retrospective study of the outcome measures employed in the Italian UK vitamin C trial identified myometric assessment of hand grip and foot dorsiflexion and the 9-hole peg test as more responsive fuctional outcome measures than the CMTNSv1 Piscosquito et al. Nevertheless, these outcome measures still had limited sensitivity SRM of 0. Clinical trials require this be predetermined for any outcome measure to be used as a primary endpoint.
It is therefore important that these specific themes be assessed in any primary outcome measure. Many of the issues identified relate to mobility, balance and distal motor and sensory loss that are incorporated in the CMTNSv2. Fatigue, pain and body image was also found to be important Johnson et al. This questionnaire contains 18 themes that identify factors related to Charcot-Marie-Tooth disease burden.
The score has been shown to have high internal consistency and test retest reliability and is able to discriminate between patients in different disease states. Efforts over the last 15—20 years have resulted in the development of several Charcot-Marie-Tooth disease specific clinical and functional outcome measures that are able to detect disease progression over 1—2 years. These scales are effective at discriminating between mild and severely affected patients Sadjadi et al.
Unfortunately, even for a highly sensitive outcome measure such as the CMTPedS, due to the intrasubject variability of the score, the number of participants required to adequately power a trial remains high Cornett et al. This has led many researchers to try and identify biomarkers of disease progression that show less variability and are more sensitive to detecting change.
As these are biomarkers, they are by definition not clinical or functional outcome measures, however the hope is that if shown to correlate strongly with clinical and functional outcome measures, they may be used as primary endpoints, enabling smaller sample sizes and the ability to detect a meaningful clinical response.
Several disease biomarkers have been identified including MRI of muscle and nerve Dortch et al. Intramuscular fat accumulation occurs as a result of muscle denervation from any neurogenic cause. Quantitative skeletal muscle MRI in which the percentage of muscle that is occupied by fat is calculated, has been shown to be a sensitive and reproducible method for quantifying the degree of disease burden in CMT 1A and hereditary sensory neuropathy type 1 Kugathasan et al.
Using the three-point Dixon MRI of skeletal muscle at calf level, an increase in muscle fat fraction of 1. Muscle fat fraction quantification in CMT1A has also been shown to be a reproducible method across two different sites further supporting its use in multicentre international clinical trials Morrow et al. One of the main criticisms directed against muscle fat fraction as an outcome measure is that is not clinically relevant.
Although muscle MRI is a sensitive and reproducible clinical outcome measure, it is expensive and time consuming which may limit its use in very large international clinical trials.
Federal Government. Read our disclaimer for details. First Posted : April 21, Results First Posted : July 28, Last Update Posted : July 28, Study Description. Part 1 is non-randomized, open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.
Detailed Description:. Part 1 non-randomized, open-label, dose-escalation Part 1 will consist of up to 3 cohorts of 6 patients each and will evaluate multiple ascending dose levels of ACE administered bilaterally once every 3 weeks for up to 5 doses in the tibialis anterior TA muscle.
FDA Resources. Arms and Interventions. Part 1 - Recombinant fusion protein. ACE mg IM tibialis anterior muscle , once every 3 weeks for up to 5 doses. ACE up to mg IM tibialis anterior muscle , once every 3 weeks for up to 5 doses. ACE up to mg IM tibialis anterior muscle or placebo, once every 3 weeks for up to 9 doses.
ACE up to mg IM tibialis anterior muscle , once every 3 weeks for up to 8 doses. Outcome Measures. The percent change from baseline in volume of injected muscle, by MRI compared to the Day Assessment is reported. Percent change from baseline in functional assessments, as measured by 6-minute walk distance when compared to Day Assessment, is reported. Change from baseline in static and dynamic balance, as measured by the Berg Balance Scale, a item scoring system to assess balance and fall risk in adults.
Percent change was calculated for the difference from baseline and Day Assessment scores on the Berg Balance Scale. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Females of childbearing potential must have negative urine pregnancy test prior to enrollment and use highly effective birth control methods during study participation and for 8 weeks following the last dose of ACE The investigators evaluated the levels of irisin in patients affected by an hereditary motor and sensory neuropathy, namely Charcot-Marie-Tooth disease CMT , in order to investigate possible key determinants of their muscle quality and possibly prevent the progressive distal weakness and muscle atrophy.
Detailed Description:. Currently, there are no effective treatment approaches for CMT other than treating symptoms with medications such as nonsteroidal anti-inflammatory drugs that provide relief of lower back or leg pain. Benefits of exercise on the musculoskeletal system are widely recognized as primary non-pharmacologic intervention for several diseases. The positive outcome of physical activity is achieved not only by the mechanical load applied on the musculoskeletal system, but also via biochemical signals, the myokines, secreted during contraction that act locally or systemically on several body districts.
Among these, Irisin is a hormone-peptide synthesized from skeletal muscle performing key actions on the whole-body metabolism. In humans, the investigators have documented with several studies an existing positive association between circulating levels of Irisin and bone mineral density. Very recently, in muscle biopsies of older adult subjects, the investigators also observed that the expression of the Irisin precursor, the fibronectin type III domain-containing protein 5 FNDC5 , was positively associated with Irisin serum levels and osteocalcin mRNA expression in bone biopsies, indicating a strong correlation between healthy muscle and bone tissues.
In humans, low levels of circulating Irisin have been found to be predictive of muscle weakness and atrophy, and Irisin has been identified as a sensitive molecular biomarker for sarcopenia in postmenopausal women. In addition, women older than 65 years undergoing a week exercise program showed an increase in circulating Irisin and an improvement in isokinetic leg strength and grip strength compared with control women. Moreover, there was a positive correlation between Irisin levels with grip strength and leg strength in the exercise group, suggesting a causal relationship between improved muscle strength and increased Irisin concentration.
Although numerous reports recommend increasing muscle strength in CMT patients to prevent progressive distal weakness and muscle atrophy, few studies have investigated the possible key determinants of muscle quality in these patients. Therefore, the aim of this study was to evaluate circulating Irisin levels in a population of 20 CMT patients as well the association of Irisin with biochemical parameters and muscle quality. In addition, the investigators compared these data with unpublished data previously obtained in healthy subjects.
FDA Resources. Serum samples were assayed for calcium, phosphorus, magnesium, iron, lactate dehydrogenase Ldh , creatine phosphokinase Cpk , creatine kinase myocardial band Ckmmb , myoglobin, thyroid stimulating hormone TSH , 25 OH -Vitamin D, osteocalcin, bone alkaline phosphatase b-ALP , C-terminal telopeptide of type I collagen CTX-I , haptoglobin, sclerostin, myostatin, and Irisin. Outcome Measures. Muscle mass determined by bioelectrical impedance analysis. Muscle quality determined by bioelectrical impedance analysis.
Correlation determined by Pearson's correlation for linear regression analysis. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. All patients with Charcot-Marie-Tooth disease who have given informed consent.
Inclusion Criteria: Definitive diagnosis of Charcot-Marie-Tooth disease Exclusion Criteria: osteoporosis intestinal malabsorption chronic inflammatory diseases chronic renal failure severe heart failure neoplastic diseases. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.
Layout table for investigator information Principal Investigator: Michele Barone, prof. University of Bari. More Information. Curr Treat Options Neurol.
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