Ongoing clinical trials for rare conditions globally are scarce in number. Rare conditions, though individually rare, are numerous overall and affect about 6% of the world’s population (~446 million individuals). There are an estimated 8000 rare conditions, with 80% being due to a genetic cause, and up to 75% having a paediatric onset. Rare conditions do not have a cure, but symptoms are managed and treatment options are very limited. In addition, rare conditions are clinically heterogenous, even within the same family, and their prevalence is uneven across the world, making them significantly more challenging to research compared to common conditions. Lysosomal storage disorders (LSDs) face further challenges as 'ultra rare' (affecting less than 1 in 50,000 people) conditions. Individuals affected by LSDs develop multisystem disease because of lysosomal dysfunction leading to the toxic build-up of substrates in various organs. Neuronopathic LSDs (nLSDs) have central nervous system involvement and are often characterised by neurodegeneration. Most individuals with nLSDs will present with developmental delay and/or regression and progressive neurological symptoms, with the most severe infantile forms being life-limiting. The need to improve the number and quality of clinical trials for nLSDs is therefore evident.
Regular systematic reviews undertaken by the COMET initiative indicates that there are only a small number of COS developed for rare genetic conditions despite there being ~8,000 rare conditions identified to date. As it would be unrealistic to develop a COS for each rare genetic condition, we aim to develop a COS for clinical trials for a group of ultra rare genetic conditions - six nLSDs (Gaucher Disease Type 2, GM1 Gangliosidosis, Late-onset GM2 Gangliosidosis, Mucopolysaccharidosis Type II, Mucopolysaccharidosis Type IIIA and Niemann-Pick Disease Type C). These nLSDs have a number of overlapping clinical features, including having a paediatric onset, and are significantly life-limiting without treatments being developed via clinical trials.
In addition to their overlapping clinical manifestations, these nLSDs have been selected due to our advantageous professional collaboration with clinical experts and researchers and access to engage with patients with these ultra rare conditions and their families at Manchester University NHS Foundation Trust. Our collaborative ties allowing engagement with these stakeholders will help in developing a useful COS by selecting outcomes that are meaningful and relevant to these stakeholder groups.
In developing one COS for a small number of conditions for clinical trials, our expectation is that it will be applicable to these six nLSDs, with the potential to diverge with the differing clinical features of these conditions in relation to the clinical trial being developed for each one.
Need for a new COS: On review of the COMET database, we are aware that there are three relevant studies that have an overlap with our conditions of interest. It will be very useful to see if there is an overlap between the outcomes identified by us and the COS developers below, once our study has been completed. Given that all these conditions are ultra rare with a very small number of patient/carer stakeholders, overlap in outcomes in this case, would strengthen the usefulness of all the COS/dataset below, rather than be considered research waste. Our rationale for why we think our new COS is still needed is as follows:
Study 2910: (A global neuronopathic gaucher disease registry (GARDIAN): a patient-led initiative). This is a dataset of clinical and patient-relevant outcomes to fill in gaps in knowledge for health care professionals to care for patients with neuronopathic Gaucher Disease. Although a very useful dataset, it is not a COS for clinical trials, and further, covers both Gaucher Disease type 2 (GD2) and Gaucher Disease type 3 (GD3). While both subtypes show neurodegeneration, GD2 is rarer, often presenting with neurological symptoms before the age of 6 months, and shows rapid but variable deterioration, with death usually around two years of age. GD3 has a broader spectrum of symptoms, and while symptoms can present in infancy, affected individuals can experience neurological symptoms only in adulthood. The purpose of use of this minimum dataset is different to the COS we propose to develop, which will focus on GD2 as part of the group of nLSDs for clinical trials.
Study 1295: (Core Outcome Set for Head, Neck and Respiratory Disease in Mucopolysaccharidosis Type II). This COS for MPS II specifically focuses on only head, neck and respiratory disease symptoms of this condition. Whilst this COS will be relevant to our work, we still believe our new COS is needed as the scope is broader, and will focus on all clinical aspects of MPS II along with five other nLSDs.
Study 1924: (Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys). This is a study protocol to develop a COS for MPS, ongoing work which will be relevant to our own. There are seven distinct clinical types of MPS, and numerous subtypes; the COS developers aim to develop a COS for all types of MPS. Our work will focus on two types - MPS II and MPS IIIA as part of the group of nLSDs for clinical trials.
Ms Zelpha D'Souza: NIHR Manchester BRC PhD student - University of Manchester, Registered Genetic Counsellor - St Mary's Hospital, Manchester University NHS Foundation Trust, UK
Professor Jamie Kirkham: (Primary PhD supervisor) Professor of Biostatistics, Head of the Division of Population Health, Health Services Research and Primary Care - University of Manchester, UK
Dr Ramona Moldovan: (Co-PhD supervisor) Senior Lecturer - University of Manchester, Principal Clinical Psychologist and Principal Genetic Counsellor - St Mary's Hospital, Manchester University NHS Foundation Trust, UK
Dr Jack Wilkinson: (Co-PhD supervisor) Senior Lecturer - University of Manchester, UK
Dr Aimee Donald: Consultant Paediatric Neurologist - Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Honorary Senior Clinical Lecturer - University of Manchester, UK
Dr Catherine Breen: Consultant Clinical Geneticist - St Mary's Hospital, Manchester University NHS Foundation Trust, Deputy Clinical Director - North West Genomic Medicine Service Alliance, UK
Dr Tara Clancy: Senior Lecturer - University of Manchester, Honorary Consultant Genetic Counsellor and Research Consultant - St Mary's Hospital, Manchester University NHS Foundation Trust, UK
Dr Andrada Ciuca: Postdoctoral Researcher - Babes-Bolyai University, Cluj-Napoca, Romania
Disease Category: Genetic disorders
Disease Name: Neuronopathic lysosomal storage disorders
Age Range: 0 - 18
Sex: Either
Nature of Intervention: Any
- Charities
- Clinical experts
- Consumers (caregivers)
- Consumers (patients)
- Families
- Patient/ support group representatives
- Researchers
- COS for clinical trials or clinical research
- COS for practice
- Consensus meeting
- Delphi process
We aim to generate the long list of outcomes by searching clinical trial protocols and summaries, published literature, online databases along with interviews with patients/caregivers and health care professionals. The extracted outcomes will be placed into appropriate domains and then rated and prioritised via the Delphi technique and a consensus meeting to form the final COS.