Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03211624 |
| Other study ID # |
CognCush |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2017 |
| Est. completion date |
December 31, 2025 |
Study information
| Verified date |
September 2023 |
| Source |
Göteborg University |
| Contact |
Oskar Ragnarsson, MD, PhD |
| Phone |
707292228 |
| Email |
oskar.ragnarsson[@]medic.gu.se |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This is a prospective, multi-center, case-control study where neurocognitive function will be
evaluated in 36 patients with Cushing syndrome (CS) and 36 controls matched for age, gender
and education.
Description:
1. Background
Endogenous Cushing's syndrome (CS) is the collective name for several rare disorders of
chronic glucocorticoid (GC) excess. The most common causes are ACTH producing pituitary
adenoma [Cushing's disease (CD)], cortisol producing adrenal adenoma (CPAA) and ectopic
ACTH producing tumors.
Cognitive dysfunction, psychiatric disorders, fatigue, and impaired quality of life
(QoL) are frequently observed in patients with active CS. Morphological changes in the
central nervous system have also been reported in patients with CS, including decreased
total brain volume and hippocampal formation volume compared with healthy subjects.
After successful treatment of CS, cognitive function improves according to some studies
while others have found no change from pre-treatment levels. Increased brain volume has
also been reported following treatment, although not to the levels of a normal control
group.
Various aspects of the neurocognitive consequences of hypercortisolism have been studied
in recent years. However, a major limitation of most previous studies is the small
sample size. Longitudinal research data is sparse. A further limitation is that CS is a
heterogeneous disease with several etiologies, varied clinical findings at presentation
and varying outcome after treatment. Consequently, and since CS is a rare syndrome, the
number of patients needed to be studied is too large for a single center. A
collaborative multi-centre effort is therefore a desirable approach.
2. Aim
The overall aims of this project are 1) to improve our understanding of CS, in
particular the spectra and time course of impaired well-being, fatigue and cognition, 2)
to study the mechanisms behind the apparently long-term negative consequences on the CNS
in these domains after biochemical remission has been achieved. For this purpose, the
investigators will use the following tools:
- Structural MRI. To evaluate total brain volume and volume of structures important
for cognitive function such as hippocampus and frontal cortex.
- Diffusion Tensor Imaging (DTI). To evaluate structural connectivity and integrity
of white matter
- Resting state and task related functional MRI (fMRI). To evaluate brain functional
connectivity during rest and during testing of cognitive and emotional functioning.
Primary regions of interests are the hippocampus, the frontal cortex and other key
regions of the limbic circuitry.
- Fludeoxyglucose Positron emission tomography (FDG-PET). To study glucose
utilization in the above mentioned brain regions.
- CSF analysis. To understand the significance of inflammatory and neurodegenerative
biomarkers in CSF and blood in patients with CS.
- Genetic and epigenetic analysis. To evaluate the influence of polymorphisms in the
GC receptor gene, and genes involved in metabolism and transport of GCs, on
cognitive and emotional functioning in patients with CS.
3. Design
This is a prospective, case-controlled study, conducted at three centres:
- The Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg,
Sweden.
- The Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain.
- The Department of Medicine, Division of Endocrinology, and Leiden Institute for
Brain and Cognition/Department of Psychiatry, Leiden University Medical Center,
Leiden, The Netherlands.
Patients and matched controls will be recruited at each centre.
The patients will be studied prior to medical and surgical treatment (baseline visit 0)
and 3, 6, 9, 12, 18 and 24 months after surgical treatment. The controls will be studied
on two occasions, namely at baseline and after 12 months.
4. Subjects Thirty-six patients with newly diagnosed endogenous CS and 36 matched controls
will participate in the study.
Since CS is a rare disorder the investigators estimate that it will take 3 years to
include 36 patients.
5. Methods
5.1 Inclusion
The study investigators at each individual centre will identify patients with newly
diagnosed CS. Inclusion will take place before any intervention, including medical
treatment for hypercortisolism.
5.2 Questionnaires
Questionnaires will be completed by patients at the individual centres in the morning
9-12 am, prior to treatment and 6, 12 and 24 months after treatment. Controls will
complete the questionnaires at baseline and after 12 months.
1. The fatigue impact scale (FIS) will be used to evaluate fatigue.
2. The EuroQol and CushingQoL will be used to evaluate quality of life.
3. The Beck Depression Inventory and Beck Anxiety Inventory will be used to evaluate
depression and anxiety
4. The apathy scale will be used to evaluate apathy.
5.3 Cognitive function
The Rey Complex Figure will be used to test memory. Digit symbol-coding from the WAIS-IV
NI will be used to assess information processing speed. Auditory attention and working
memory will be measured by the digit span test. The verbal fluency test (FAS) will be
used to measure the ability to generate as many words as possible beginning with a
specific letter within 1 minute.
5.4 Structural MRI (Magnetic Resonance Imaging)
Patients will undergo cranial magnetic resonance imaging before treatment as well as 12
and 24 months after surgery. Control subjects will be scanned twice with an interval of
approximately 12 months. In line with previous MRI studies in patient populations, total
time for participants in the scanner will be one hour or less.
5.5 Diffusion Tensor Imaging (DTI)
The investigators will also acquire DTI data along 32 directions, enabling analyses of
integrity as well as fibre tracking.
5.6 Functional MRI
Functional MRI will be used to study resting state functional connectivity as well as
brain activity during cognitive and emotional function prior to treatment, and 12 and 24
months after treatment.
5.7 Positron emission tomography
Resting state glucose utilization in the brain will be studied by using fludeoxyglucose
positron emission tomography (FDG-PET) prior to treatment and 12 months after treatment
(only in patients from Gothenburg). Controls will be studied with FDG-PET only at
baseline.
5.8 Neurodegenerative and inflammatory biomarkers in CSF and blood
Neurodegenerative and neuroinflammatory CSF markers, as well as peptides and hormones
important for GC metabolism, will be analysed prior to treatment and 12 months after
treatment (only in Gothenburg). Controls will be studied only at baseline.
5.9 Genetics
Polymorphism in the GC receptor gene, and other genes involved in metabolism and
transport of GCs will be analysed in all subjects at inclusion in the study. All genetic
analysis will be performed at Sahlgrenska University Hospital, Gothenburg, Sweden, in a
single run at the end of the study.
Blood samples for DNA and RNA will be collected at baseline and 24 months after
treatment for analysis of methylation and mRNA expression.
6. Ethical considerations
The study will be conducted according to the Declaration of Helsinki. Application for
Ethical approval will be applied from the local ethical committees in Barcelona,
Gothenburg and Leiden. Informed written consent will be obtained from all patients and
controls. Incidental findings of clinical significance will be investigated further by
the respective participating centers.
7. Statistical methods - Power calculations A power analysis based on previous results from
studies on cognitive function as well as fMRI findings in patients with Cushing syndrome
suggests that between 14 and 28 subjects need to be included in the study to detect a
difference between patients with CS in remission and controls with a significance level
of 5% and power of 80%. Because multiple comparisons will be applied, comparing brain
activity between different groups on three performance tasks as well as a resting state
condition, 36 participants per group will be included.
8. Financial disclosure
An unrestricted grant has been provided by HRA Pharma.
