Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04991701 |
| Other study ID # |
16069 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 14, 2018 |
| Est. completion date |
December 31, 2022 |
Study information
| Verified date |
October 2021 |
| Source |
University of Nottingham |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This is a retrospective observational study of natural-history of ataxia-telangiectasia.
Understanding the natural history and its variability is not only vital to planning effective
patient-centred services, and counselling patients and their families, but will also inform
the design of future clinical research, particularly clinical trials.
Description:
Ataxia Telangiectasia (A-T), a life shortening autosomal recessive multisystem disease, is
caused by mutations in the ATM gene, and affects 1/300,000 live births. The
pathophysiological basis of the disease relates to mutations in the ATM kinase gene that
result in a faulty repair of breakages in double-stranded DNA. A-T causes a progressive
ataxia, dystonia, and movement disorder, and is complicated by immunodeficiency, lung
disease, faltering growth, limb and spinal deformities, and increased susceptibility to
cancers. The disease first manifests in early childhood with balance problems and is slowly
progressive, with loss of control of limb and eye movements, and speech, through the school
years, resulting in severe disability by adulthood. Patients with classical A-T rarely live
beyond their 20s, and there is no effective treatment. Because it is so rare, little has been
published on the natural history of the condition.
The Department of Health funds the national multidisciplinary clinic for children with A-T in
Nottingham, with follow-up of adults at the Royal Papworth Hospital, Cambridgeshire. Clinical
and laboratory data have been collected systematically from over 170 patients, most on more
than one occasion, from 2001 to date. This unique clinical collection will allow us to
elucidate the natural history of A-T using a mixture of cross-sectional and longitudinal
analyses, from presentation in the pre-school years to adulthood.
We will discover more about the presentation and diagnosis of A-T, and the detailed evolution
of the disease as children grow to adulthood. Preliminary analyses of the neurological
phenotype in 134 patients has shown important genotype-phenotype relationships and a more
variable deterioration over time than anticipated, which will be investigated further. In
parallel, investigation of the morbidity and mortality due to deterioration in lung function,
the immune system, infections, cancers, malnutrition, and skeletal deformity will be
undertaken. We will learn about the interactions between the various disease manifestations,
e.g. lung disease and nutritional status, immunological impairment and neurology and risk of
cancers. These discoveries will inform patient care, and help to generate hypotheses for
further research projects. From the analysis of the cross-sectional data we will establish an
initial Core Outcome Set, which will be further developed at Patient and Public Involvement
(PPI) meetings with young people with A-T and their parents/carers.
This study is needed to accurately map the course of A-T from childhood to adulthood, to help
us recognise different patterns of disease in individual patients, improve early diagnosis by
understanding the reasons for diagnostic delay, anticipate complications more accurately and
elucidate the best ages to intervene before rapid deterioration.
The expected clinical course involves deterioration in gross and fine motor skills,
oculomotorpraxia, choreoform movements, and difficulty with chewing and swallowing. By the
end of their first decade children are usually wheelchair dependent as cerebellar destruction
progresses and further neurodisability ensues with development of incapacitating movement
disorder and peripheral neuropathy. Sinopulmonary infections and recurrent lower respiratory
tract infections with bronchiectasis are common in A-T, and current management aims to avoid
and treat lung infection. The treatment for malignancy must take into consideration the fact
that many oncological therapies have adverse-effects that will impact on individual function
in other domains for example drugs that cause muscle weakness will exacerbate motor
impairments. Also the DNA of patients with A-T is particularly susceptible to double strand
breakage, which can itself cause secondary malignancies.
Understanding the natural history and its variability is not only vital to planning effective
patient-centred services, and counselling patients and their families, but will also inform
the design of future clinical research, particularly clinical trials. The choice of age group
to include in a trial, duration of treatment, and choice of core outcome measures will depend
on the results of this natural history study.
This study will centre on data analysis and will not involve any therapeutic interventions,
although it is intended that the results will enable future research to determine optimum
therapeutic strategies. The benefits of this study thus relate to the compilation of vast
amounts of data that have been gathered on A-T over the last 15 years and extracting
meaningful information that will inform future care. There is no identifiable risk from
inclusion in the study as it involves patient data that are gathered through standard
clinical interaction and does not involve introducing or changing treatments or any increased
patient interaction apart from voluntary participation of a sample of parents / guardians and
young people with A-T in the PPI focus group meetings, for which informed consent will be
sought.
There are no established treatments for A-T. Symptomatic treatments are used in patients
depending on their symptoms, e.g. gastrostomy feeds are used when eating becomes too slow, or
too difficult because of swallowing difficulties. Antibiotics and chest physiotherapy are
used to prevent and treat chest infections. Immunodeficiency can be treated in selected
cases, as can the various complications of A-T as and when they arise, including scoliosis,
cancers, granulomas, movement disorders and spasticity.
Current therapy in A-T is aimed at mitigating neurological deterioration, prevention and
treatment of respiratory complications, early identification and treatment of malignancy
whilst minimising adverse-effects and treating immunodeficiency with immunoglobulin, in other
words, managing the downstream complications of the gene mutation. Each aspect and
complication requires specialist assessment and input and monitoring of progression and
response to treatment. A-T is managed from a multi-speciality and multi-disciplinary
perspective and in Nottingham this happens in the setting of the National A-T Clinic that
children attend with their families every two years. Neurological progression is determined
using the A-T Index and AT-NEST scoring systems. Assessment by a clinician with paediatric
respiratory expertise also occurs alongside input from a neurologist, immunologist,
geneticist, dietician, occupational and physiotherapist, clinical psychologist and speech and
language therapist. One of the aims of this natural history study is to avoid complications
developing by elucidating the optimal timing of treatment interventions.
Respiratory disease patterns in A-T include sinopulmonary disease and bronchiectasis,
interstitial lung disease and lung disease associated with neuromuscular, especially bulbar,
dysfunction. At present treatment depends on the pattern of lung disease and can range from
antibiotics, immunoglobulin replacement, systemic steroids, chest physiotherapy, and steps to
limit aspiration. Assessment of response to treatment includes assessment of resolution or
persistence of symptoms, spirometry measurements, and imaging such as chest x-rays and where
indicated, CT scans, although limiting exposure to radiation is always a factor to consider
in patients with A-T.
There have been several small scale pilot trials of medication for the neurological
impairments with mixed success, including the use of amantidine5, betamethasone6,7, and
dexamethasone loaded autologous redcells8.
Potential but as yet untested treatments include anti-oxidants which have the potential to
slow down progression of neurodegeneration by protecting Purkinje cells in the cerebellum
from oxidative stress caused by free radicals. ATM has a role in the inhibition of oxidative
stress and absence or reduced function of ATM could result in increased oxidative stress and
accelerated neuronal loss.11
However, all these suggestions in fact impact the downstream consequences of the mutations.
In cystic fibrosis, another multisystem genetic disease which largely impacts the respiratory
system, the treatment paradigm has shifted from downstream treatment of the consequences of
gene dysfunction, to gene therapy and small molecule treatments addressing the basic defect.
It is likely that in the near future A-T will follow this paradigm, e.g. with the development
of drugs to allow read-through of premature termination codons, or the skipping of mutations,
or the incorporation of functioning genetic sequences into the genome. These and other, as
yet unknown, therapeutic approaches will require carefully designed clinical trials, and this
natural history study will inform the design of such future trials.
The study will allow a systematic approach to A-T and an understanding of the progression of
respiratory, neurological, immunological and oncological disease that underline this
multi-systemic disorder, as well as the impact of growth impairment. It will enable
evaluation of procedures and medical treatments as well as surgical therapies. There will be
insight into the psychological impact of the illness of children and their families and
whether there is a particular period where increased or additional support needs to be
offered.
As discussed earlier, a critical outcome will be determining the timing of appropriate
therapeutic interventions to prevent complications and delay progression of disease, as well
as the potential to inform the design of future clinical trials involving therapies for A-T.
As a natural history study there will be scope to extract information about A-T within all
domains and identify any important variables in treatment, identify whether timing of
treatment needs adjustment for maximal impact, for example, by earlier introduction of
therapy there may be slower progression of disease or fewer complications.
A possible negative consequence is that the information gleaned might be of little immediate
clinical use, however we do not think that will be the case. We think that the data will be
valuable in highlighting evidence gaps and informing new studies. We may find that there are
inconsistencies in treatments offered to patients and which will encourage us to try to
rationalise and streamline our clinical assessments and advice.
