StartRIGHT: A Pilot Research Study About Diabetes Diagnosis & Treatment
StartRIGHT: A Pilot Research Study About Diabetes Diagnosis & Treatment
This study aims to achieve more accurate early classification of diabetes and identification
 of which patients will rapidly require insulin treatment. The investigators will recruit 1000
 participants who have been diagnosed with diabetes in the last year and were aged between 18
 and 50 years at the time of diagnosis. The investigators will recruit an additional cohort of
 400 participants diagnosed after age 50 treated with insulin at recruitment. The
 investigators will record clinical features and biomarkers that may help us to determine
 diabetes type at diagnosis and follow participants for 3 years to assess the development of
 severe insulin deficiency (measured using C-peptide) and insulin requirement. The
 investigators will assess utility of clinical features and additional biomarkers in
 identifying patients with rapid progression to insulin requirement. Findings will be
 integrated into a freely available clinical prediction model.
Diabetes is stratified into recognised subtypes with major implications for patients'
 treatment. The treatment of Type 1 diabetes (T1D), Type 2 diabetes (T2D) and Maturity-onset
 diabetes of the young (MODY) is markedly different and based on clear differences in
 underlying pathophysiology. The difficult part of this stratification is correctly diagnosing
 the subtype especially in young adults. The clear differentiation of T1D as slim and young,
 and T2D as obese and old, no longer holds with the rapid increase in obesity in the
 population: T1D patients may be obese and T2D patients may be diagnosed young. 90% of MODY
 patients are misdiagnosed with T1D or T2D as the diagnosis of MODY is rarely considered. This
 results in 7-15% of young adults with diabetes being wrongly classified and incorrectly
 treated. Initial clinical diagnosis is not systematic and once made is rarely changed.
 Misdiagnosis of T2D or MODY as T1D results in unnecessary initial insulin treatment leading
 to higher drug/monitoring costs, more side effects (weight gain, hypos), and patient
 inconvenience/dissatisfaction. Misdiagnosis of T1D as T2D, or MODY (initial treatment
 diet/tablets), results in poor glycaemic control, frequent contact for increased treatment,
 inappropriate insulin regimes and the risk of life threatening ketoacidosis.

 The investigators have developed an optimized diagnostic strategy (ODS) based on integrating
 Clinical information (a validated clinical probability model), Biomarkers (GAD, Islet
 antigen-2 (IA2) and ZnT8 autoantibodies) and Genetic testing for MODY. This has the potential
 to determine the subtype of diabetes in young adults leading to improved treatment and care.
 Prior to undertaking a comprehensive RCT to test our ODS against standard care, the
 investigators must first undertake this pilot study to assess the feasibility of such a
 project.

 Objectives: To assess the feasibility of recruitment and retention for a proposed large scale
 RCT, optimize recruitment and retention strategies, develop and assess the protocols and
 procedures, test delivery of the ODS, assess the impact of the ODS and obtain pilot data to
 inform sample size calculations for the proposed RCT Potential participants will be
 identified from routine clinical care, with clinicians informing patients of the project in
 general terms and seeking permission for their contact details to be passed to the research
 team. A range of referral strategies will be assessed and all potential participants who
 appear to meet the entry criteria will be invited to participate.

 Referral strategies to be assessed will include: referral to research team by GP/ Practice
 Nurse/diabetes specialist nurse, regular GP practice database searches, via pathology lab
 following raised Hba1c Initial visit (I hour): Participants will meet with a member of the
 research team who will obtain consent and collect baseline blood samples, demographic and QoL
 data. Participants will be randomised to either the intervention or control arm using a
 computer generated randomisation schedule. For participants in the intervention arm the blood
 samples will be analysed at the Royal Devon &Exeter National Health Service Foundation Trust
 (RD&E NHS FT) Biochemistry Department for HbA1c, C-peptide and islet autoantibodies (GAD, IA2
 and ZnT8) with DNA extracted and stored for genetic testing if appropriate. These blood
 results will then be immediately incorporated into the ODS for feedback to Clinicians and
 participants with recommendations that appropriate national guidelines for the ODS diagnosis
 (e.g. NICE guidelines for Type 1 or Type 2 diabetes) are followed. For participants in the
 control arm their current clinical features will be recorded and their blood samples will be
 stored for future analysis. At the end of their involvement in the study, both recorded
 clinical features and results from stored blood samples will then be and incorporated into
 the ODS for feedback to both clinicians and participant.

 Follow up (6 monthly intervals over 3 years): Participants will then be followed up at 6
 monthly intervals over a 3 year period (choice given of text, phone, or email) to maintain
 participant engagement and enable collection of details of current treatment, treatment
 changes and frequency of hypoglycaemia. Results from routinely collected HbA1cs will be
 obtained from clinical practice.

 At 3 years, participants will be seen again by the research team for collection of a further
 blood sample, details of final treatment and quality of life measures. This will end their
 participation. At the end of the study individual results from the ODS for those in the
 control (standard care) arm will be generated and fed back to clinicians and participants.

 All participants will be assigned a unique study ID. All data collected will be recorded and
 stored under this ID number. Data will be initially recorded onto a study specific data
 collection form (DCF). Data will then be recorded onto a study specific database.
 Hard/scanned copies will be stored in the study specific site file. Data will be screening
 for discrepancies and missing data prior to analysis.

 Baseline data will include: personal identifiers, anthropometry, diabetes and medication
 history and blood biochemistry. Permission will be obtained to access medical notes should
 this be required for diabetes data relevant to taking part in the project.

 All participant data will be held in a link-anonymised format, Participants' research and
 sample data will be identified by unique study ID numbers and all data will be held on
 password-protected computers. Only the CI or designated research team member will have access
 to personal identifiable data.

 Data Storage and Archiving: All consent and paper data collection forms will be scanned onto
 discs and stored in locked filing cabinets within the controlled access ECRF for the duration
 of the project. Paper copies will be shredded. Should a full RCT be developed from this
 project participant data and samples will be transferred and used for analysis in the larger
 study. If at the end of this study the RCT has not yet been commenced, remaining samples and
 data will be transferred for safe keeping to the Peninsula Research Bank (PRB).

 Sample analysis: Blood samples will be analysed for HbA1c, C-peptide and islet autoantibodies
 (GAD, IA2 and ZnT8) on site at the RD&E NHS FT blood sciences department. DNA will be
 extracted and stored for genetic testing if appropriate.

 Primary Outcome measures:Time to optimum treatment following diagnosis. Optimum treatment
 will be determined at 3 year follow up on the basis of whether insulin is required or not
 (using C peptide testing if on insulin and HbA1c testing if not on insulin). If insulin is
 not required then the optimum treatment will be determined using the treatment guidelines for
 T2D or the subtype of MODY diagnosed. Treatment will be recorded 6-monthly up to 3 years.

 Secondary outcome measures: Mean glycaemic control over the first 3y after diagnosis, patient
 satisfaction, number of hypos, weight change.

 Statistics and Power Calculations The aim of this study is to determine feasibility for a
 future RCT, not to determine clinical differences. The investigators have therefore taken a
 pragmatic approach based on the number of potential recruits available over a one year
 period. The investigators estimate 220 people are diagnosed per year in Exeter and
 surrounding area. The investigators will invite all patients who fulfil the entry criteria to
 participate. This will enable us to determine a realistic recruitment rate and obtain
 estimates of rates of misclassification to inform the full RCT. Therefore, analysis will be
 restricted to descriptive statistics only

 Ethical considerations: The investigators have discussed the potential ethical considerations
 with members of our PRB steering committee and addressed them as follows:

 Blood sampling: a routine part diabetes care, may result in slight pain and bruising, risks
 minimized by sampling undertaken by staff experienced in venepuncture procedures. Patient
 burden: participation involves 2 blood samples (3 years apart) and 5 follow up contacts over
 the 3 year period (via participant choice of phone/e-mail/text). This was not considered
 unduly burdensome. Immediate/delayed ODS feedback: following considerable discussion around
 the acceptability of immediate or delayed feedback of results from the ODS, our lay members
 felt that considering all participants would receive treatment based on current clinical and
 NICE guidelines the delay in feedback of ODS results would be acceptable.

 Subject Withdrawal: Subjects will be informed that they are free to withdraw from the study
 at any time up until the samples and data are coded but not anonymised. When samples are
 fully anonymised, the participants will still be able to withdraw but their samples and
 associated data will be retained for use in analysis.

 Study Management:The study will be managed by the National Institute of Health s Research
 (NIHR) Exeter Clinical Research Facility providing infrastructure support and facilitate
 recruitment and sample collection.

 Timescale: 4 years. This is a relatively long time for a pilot study and is necessary to
 enable data collection from each participant, over a 3 year period, to provide a clinically
 relevant definition of optimal treatment.

 All costs will be met by existing research funding:

 Sample analysis costs (HbA1c/Serum c-peptide, islet autoantibodies (GAD, IA2 and ZnT8) and
 Genotyping where appropriate) will be covered by the CI's existing Welcome Trust senior
 Investigator award. Service support costs will be provided by the NIHR Exeter Clinical
 Research Facility.

 Project development and user involvement: The study team will have access to the user
 representative group of the NIHR Exeter Clinical Research Facility (ECRF). In keeping with
 the NHS Patient Carer and Public Involvement (PCPI) strategy the ECRF invites user
 representatives to contribute to the development of various projects within its portfolio.
 These individuals have agreed to maintain contact and regular meetings have been established
 at which researchers discuss the development of current projects within the ECRF.

 Reporting adverse effects: This is a low risk study and it is not anticipated that
 participants involved in this project will be subject to adverse effects, other than slight
 bruising from blood sample collection. The CI will be informed of any adverse effects within
 24 hours and they will be reported following local NHS R&D SOPs with a copy of any adverse
 event form stored in the project site file.

 Participant Feedback: Depending on the randomization arm feedback from the ODS will be fed
 back to participants and their GP immediately or at the end of the study. Should any
 biochemistry immunological or genetic result potentially impact on clinical care, the results
 will be initially discussed with the ECRF Clinical Director and a decision may be made to
 contact that individual participants GP or healthcare team. A statement to this effect is
 included in the consent form.

 Dissemination/implementation of research: Results will be written up and submitted for
 publication in a peer-reviewed journal. Abstracts will be submitted to national and
 international conferences.

 Potential impact and benefit of the research: short term- the investigators hope to obtain
 the necessary information to conduct a definitive RCT. Longer term-evidence that the ODS can
 improve diagnosis and treatment for patients diagnosed with diabetes will lead to improved
 treatment and quality of life for patients and a reduction in the NHS costs associated with
 inappropriate treatment and monitoring and complication rates.

 End of Study: the study will finish when all initial and follow up data has been collected
 and analysed on all participants.
Inclusion Criteria:

 -  Recent clinical diagnosis of Diabetes (the working definition of recent will initially
 be within 3 months, but this may be modified if required).

 -  Aged 18 - 50 yrs of age at diagnosis.

 -  Able and willing to provide informed consent

 Exclusion Criteria:

 -  Gestational diabetes

 -  Known secondary diabetes

 -  Unable/unwilling to provide informed consent