Improving the accuracy of MRI spleen and liver volume measurements: A phase III Gaucher disease clinical trial setting as a model
Introduction
Gaucher disease, the most prevalent lysosomal storage disease [1], [2], [3], is caused by mutations in the glucocerebrosidase gene (GCD), leading to a reduced activity of the lysosomal enzyme glucocerebrosidase and an accumulation of the substrate glucocerebroside in the cells of the monocyte–macrophage system. This storage leads to hepatosplenomegaly and consequent hypersplenism as well as skeletal involvement, and less frequently, lung and neurological involvement [4].
Identification of GCD deficiency as the etiology of Gaucher disease stimulated the development of the first enzyme replacement therapy (ERT) as a therapeutic strategy for this and eventually other single gene lysosomal diseases. ERT provides sufficient exogenous active enzyme to degrade the accumulated substrate in the macrophages and ameliorate the disease-specific visceral features. ERT, which has been available for Gaucher disease for nearly two decades, has been shown to be safe and clinically efficacious within 2–5 years [5], [6], [7], [8].
Clinical trials to introduce new ERTs or other therapeutic modalities in Gaucher disease have opted for multiple primary endpoints for proof of efficacy because of the need for stringent standardized criteria that are unambiguous. Since reduction in organomegaly is a clinically relevant feature of successful treatment that also translates into improvement in the hematological features, changes in spleen and liver volumes are common endpoints in clinical trials of Gaucher disease [9], [10]. Nonetheless, in designing efficacy endpoints for clinical trials in Gaucher disease, there may be confounding variables when choosing improvement in anemia or thrombocytopenia (e.g., concurrent iron-deficiency or idiopathic thrombocytopenic purpura, respectively) or reduction in hepatomegaly (especially when it is very minimal). Hence, change in spleen volume is the most ideal parameter as a marker of efficacy, but absolute accuracy in measurement would have to be proven to be independent of observer bias in order to accommodate a multi-center trial.
This paper describes a novel method to achieve a very low degree of inter-observer variability in MRI spleen and liver volume assessments as demonstrated in a phase III clinical trial of a new ERT for Gaucher disease.
Section snippets
Study methodology
The study used as a prototype for the methodology a phase III randomized double-blind parallel-group dose-ranging clinical trial involving 11 international sites that received IRB approval and recruited 31 treatment-naïve patients with Gaucher disease who consented to receive a plant-cell-derived recombinant ERT (taliglucerase alfa; Protalix, Carmiel, Israel). The single primary endpoint was reduction in spleen volume after 9 months of treatment in two-dose groups; liver reduction was a
Variability results
The variability in 178 volumes (89 each of spleen and liver) reviewed twice is presented in Fig. 5.
The mean inter-observer variability per time-point is summarized in Table 1. Overall, mean variability in spleen measurements was 0.30% compared to 0.53% for liver measurements.
Variability being less than 5% for all cases, no adjudication was required.
The outlier which can be seen at screening on both spleen and liver measurements corresponds to an examination of poor quality which could not be
Factors influencing accuracy
Given the large variety of scanners used across sites, which is inevitable in the context of an international multi-center trial, the accuracy of a cross-sectional analysis may be decreased, unless one is able to monitor the variability induced by the systems themselves and make sure it is minimal. This could be addressed by scanning abdominal phantoms multiple times at different sites. The influence of field strength would also be a subject of interest, even though here all scans were
Conclusion
A semi-automatic organ volume measurement methodology utilizing an automatic segmentation software method was found to be precise in monitoring spleen and liver volume changes over time, with a much lower variability than traditional fully manual methods. Given the observed minimal variability rates among multiple central imaging expert readers, a single read of each case would be sufficient to accurately measure spleen and liver volumes, and detect response to treatment on follow-up
Disclosures
As a contract research organization (CRO), BioClinica was selected by Protalix for managing the MRI component of their phase III study. The services performed were invoiced as stated in the CRO contract. BioClinica staff and the central imaging expert readers remained blinded to treatment groups and declared no conflicts of interest in this work. Besides, Einat Brill and Raul Chertkoff are full time Protalix employees.
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Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease
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Long-term efficacy and safety results of taliglucerase alfa through 5 years in adult treatment-naïve patients with Gaucher disease
2019, Blood Cells, Molecules, and DiseasesAssessment of the liver and spleen in children with Gaucher disease type I with diffusion-weighted MR imaging
2018, Blood Cells, Molecules, and DiseasesLong-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase
2018, Blood Cells, Molecules, and DiseasesCitation Excerpt :Exclusion criteria were presence of severe complex neurological signs and symptoms characteristic of neuronopathic GD other than long-standing oculomotor gaze palsy; any medical, emotional, behavioral, or psychological condition that would interfere with study participation; and current use of another investigational agent. Spleen and liver volumes were measured using a volumetric MRI technique employing automatic segmentation software methodology, which allows for lower variability and more precise monitoring of changes over time than traditional, fully manual methods [13]. Volume was calculated in multiples of normal (MN), where normal spleen volume is 2 mL/kg and normal liver volume is 25 mL/kg.
Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease
2015, Blood Cells, Molecules, and DiseasesCitation Excerpt :Patients were excluded based on any of the following criteria: presence of complex neuronopathic features other than longstanding oculomotor gaze palsy; unresolved anemia due to iron, folic acid, or vitamin B12 deficiency; currently taking another investigational drug for any condition; previous hypersensitive reaction to alglucerase or imiglucerase; history of allergy to carrots; inability of parents or guardians to understand the nature, scope, and consequences of study participation; and presence of any medical, behavioral, psychological/emotional condition that would, in the investigator's opinion, interfere with full participation in the study. Spleen and liver volumes were measured using magnetic resonance imaging as previously reported [15] and were assessed at BioClinica, Lyon, France. Beta-glucocerebrosidase activity, chitotriosidase or CCL18 activity, and DNA sequencing were performed at a centralized laboratory, the Academic Medical Center in Amsterdam, The Netherlands.
Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease
2011, BloodCitation Excerpt :Pharmacokinetic graphs showing a dose-dependency were comparable with those described in healthy volunteers.13 This pivotal study, with approximately the same number of patients as in the other seminal ERT trials in Gaucher disease,1-3,19 demonstrates safety of plant cell–expressed taliglucerase alfa by virtue of no serious adverse events, low rate of Ab formation, no neutralizing Abs, and a low incidence of hypersensitivity reactions, which are similar to those of imiglucerase.1-4 Nonetheless, the small sample size is a limitation of the study.