A randomised feasibility study of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes (CADOM)

doi:10.21203/rs.3.rs-1885580/v1

Aim

This study aims to explore the feasibility of using serial MRI without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot, in order to decide whether a large-scale trial is warranted

Methods

A multicentre, randomised, prospective, two arm, open, feasibility study (CADOM) of people with diabetes with a suspected or confirmed diagnosis of Charcot neuroarthropathy . Participants were randomised (1:1) to ‘standard care plus’, including repeated foot temperature measurements and X-rays, or the intervention arm, with additional three-monthly MRI, until remission of Charcot neuroarthropathy or a maximum 12 months (active phase). Participants were then followed-up for a further six months, post remission to monitor for relapse of the Charcot neuroarthropathy (follow-up phase). Feasibility outcomes were recruitment, retention, data completeness and safety of the intervention MRI. We also collected clinical, and patient reported outcomes, and data on health and social care usage to inform a future cost effectiveness analysis.

Results

One-hundred and five people were assessed for eligibility at five sites. 64/105 potential participants meet the eligibility criteria to participate in the study Forty-three participants were randomised: 20 to standard care plus and 23 to MRI intervention. The main reason for ineligibility was a previous episode of Charcot neuroarthropathy . Thirteen participants were withdrawn post-randomisation due to an alternative diagnosis being made diagnosis. Of the remaining 30 participants, 19 achieved remission, 6 had not gone into remission at the end of the 12-month active phase so exited the study. Five participants were lost to follow-up. Of the MRIs that were not disrupted by COVID-19 pandemic 26/31 (84%) were completed. As this was a feasibility study it was not designed to test the effectiveness of serial MRI in diagnosing remission. However, there was no statistical difference in the time in off-loading device between the two arms of the study: Hazard Ratio (HR) 0.405 (95% CI 0.140-1.172), p=0.096 .

Discussion

The findings support a definitive randomised controlled trial to evaluate the effectiveness of MRI in diagnosing remission in Charcot neuroarthropathy. The rates of recruitment, retention, data, and MRI completeness show that a definitive study is feasible.

Study registration ISRCTN, 74101606. Registered on 6 November 2017.

http://www.isrctn.com/ISRCTN74101606?q=CADom&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search

Charcot neuroarthropathy

Remission

Diabetes

MRI

Temperature monitoring

X-ray

Feasibility study

Monitoring and diagnosing remission in Charcot neuroarthropathy are challenging because they rely on techniques which do not accurately reflect disease progression.
Current evidence suggests Magnetic Resonance Imaging may be superior to current monitoring techniques.
This study is the first to assess the feasibility of conducting a definitive trial to evaluate the use of serial Magnetic Resonance Imaging (intervention) to reduce treatment times in Charcot neuroarthropathy.
Despite the COVID-19 pandemic, study recruitment and retention were good.
The intervention was safe, feasible and acceptable.
A definitive trial on the use of serial Magnetic Resonance Imaging in monitoring Charcot neuroarthropathy is justified.

Charcot neuroarthropathy is a relatively rare but serious complication that can affect people with peripheral neuropathy. It is most commonly diagnosed in people with diabetes, usually affecting the foot. There is uncontrolled inflammation, bones become weakened, and this can lead to fractures and joint dislocation.

In 2018 a regional survey of 205,033 people with diabetes in the East Midlands, England reported a point prevalence of 0.04%(1). Population-based studies have estimated a life time cumulative incidence for Charcot neuroarthropathy of 0.4–1.3% in people with diabetes, and 13% in those attending diabetic foot specialist clinics(2).

Usual care for people with Charcot neuroarthropathy is to offload pressure and immobilise the foot with a non-removable cast or boot(3). This aims to stop the inflammatory process, relieve pain, and maintain foot architecture(3). Studies from the UK and Brazil show a median time to remission of up to 12 months(4–6). Other studies report shorter times to remission: 3–5 months (US)(7, 8) and 3–6 months (Germany)(9).

Guidelines for Charcot neuroarthropathy management state that off-loading and immobilisation should be continued until the temperature difference between the affected and unaffected foot is less than 2°C, with no further radiological changes on X-ray(10). However, this recommendation is based on low quality level IV evidence– i.e., case series(10).

Skin temperature measured with infrared thermography is recommended as a monitoring technique in Charcot neuroarthropathy, as it involves inflammation of the soft tissue and bone. Skin temperature is a proxy measure of inflammation measured over the site of injury and may not reflect the degree of inflammation within affected bones and/or joints. X-rays show damage to the foot skeleton rather than disease activity and are a measure of foot deformity. In contrast, magnetic resonance imaging (MRI) provides detailed pictures of bone and soft tissue structures and can show abnormalities not evident on X-rays(11). Emerging evidence from case series and observational data suggests that MRI may be useful for monitoring active Charcot neuroarthropathy (12–14), and that MRIs findings could be adopted as the criterion standard for assessing disease activity and remission. However, evidence supporting a definitive trial is currently lacking. We conducted a study to assess the feasibility and acceptability of serial MRI and recruitment and retention of participants.

Aims and objectives

This study aims to explore the feasibility of using serial MRI without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot, in order to decide whether a large-scale trial is warranted.

Full details of the protocol are published elsewhere(15). This was a two arm, multicentre, open, randomised controlled feasibility study. Participants were recruited from specialist diabetic foot clinics. The study was divided into two phases. Phase one, the active phase, until the Charcot neuroarthropathy was in remission, or a maximum of 12 months. Phase two, the follow-up phase, for six months after the apparent remission of the Charcot neuroarthropathy . The study was approved by East Midlands - Derby Research Ethics Committee, 04/10/2017, ref: 17/EM/0288. All participants provided written consent.

Participants – Inclusion and exclusion criteria

Participants were aged over 18 years old with diabetes as defined by the World Health Organisation(16) and with a suspected or confirmed diagnosis of Charcot neuroarthropathy . The full inclusion and exclusion criteria are shown in Table 1. We decided to exclude people with a previous diagnosis of Charcot neuroarthropathy as new and relapsed cases of Charcot neuroarthropathy may have different healing times. We chose a cut off period of six-months based on the opinion of clinical experts within the trial management team, as we thought that this would ensure that only true news cases of Charcot neuroarthropathy were recruited to the As a confirmed diagnosis of Charcot neuroarthropathy can take several weeks, participants were recruited as early as possible to accurately collect the duration of wearing an off-loading device. This was because ‘time in cast’ is the proposed primary outcome. If the clinical team decided on an alternative diagnosis, the participant exited the study.

Table 1 – Inclusion and exclusion criteria

Inclusion Criteria	Exclusion Criteria
Participants who are willing and have capacity to give informed consent.	People who have received a transplant and others receiving immunosuppressant therapy or using long-term oral glucocorticoids other than in the routine management of glucocorticoid deficiency. Participants on a low dose of oral glucocorticoids (<10mgs for ≤7 days) are eligible to participate in the study.
People with diabetes as diagnosed by the WHO criteria	Participation in another intervention study on active Charcot.
Age 18 years or over.	Contra-indication for MRI.
New or suspected diagnosis of acute Charcot (no previous incidence of acute Charcot within the last 6 months on the same foot) treated with off-loading.	Treatment for previous suspected Charcot on the same foot in the last 6 months.
Understand written and verbal instructions in English.	Suspected or confirmed bilateral active Charcot at presentation.
	Active osteomyelitis at randomisation
	Previous contralateral major amputation.
	Inability to have an MRI scan.
	People receiving palliative care.

Abbreviations

MRI Magnetic Resonance Imaging

WHO World Health Organisation

Randomisation, blinding and data collection

Eligible participants were randomly assigned using a web-based randomisation process on a 1:1 basis to: (a) Immobilisation discontinued on the basis of clinical remission determined by skin temperature measurement, which triggered an MRI (standard care plus) or (b) Standard care plus and additionally the serial use of MRI at 3, 6, 9 and 12 months to identify disease remission and discontinuation of immobilisation (intervention).

Sample size

As this was a feasibility study a power calculation was not required. An allowance was made for 10-15% of participants to be withdrawn from the study due to an alternative diagnosis. We planned to recruit 60 people with 30 participants per arm, based on recommended sample sizes between 24 – 50 for a feasibility study(17).

Study Interventions

Standard care plus participants received usual care for assessment and management of Charcot neuroarthropathy . We standardised assessment of foot temperature to monitor Charcot neuroarthropathy by using the same device, the Thermofocus 01500A3® (Tecnimed, Varese, Italy). Every 14 days a research team member measured the temperature of both feet at five different sites. Temperatures were collected four times after removal of the off-loading device: 0, 5, 10, and 15 minutes. In this feasibility study the first reading of ≤2°C at the site overlying the CN was used as the marker for remission. At remission participants received a study specific MRI.

Intervention: In addition to standard care plus, intervention participants received serial MRIs at 3, 6, 9 and 12 months. They did not receive further MRIs once remission was diagnosed. The median time for remission of Charcot neuroarthropathy is reported as between 3-12 months, therefore we decided that the time to first intervention MRI should reflect the shortest reported median time to remission. As this was a feasibility study, we did not seek to standardise the MRI sequencing protocol.

Study procedures

The schedule of enrolment, interventions and assessments is shown in Supplementary figure 1. Potential participants were approached when attending their regular foot clinic appointment. After giving written informed consent) participants attended visits every 14 days until remission. Participants received usual care for Charcot neuroarthropathy regardless of randomisation arm. At each visit foot temperatures were measured, and clinical outcomes such as new ulceration, foot infection, and amputation (major and minor) collected. Participants received a patient diary every fortnight to record all health and social care use. Patient-reported outcome questionnaires (EQ-5D-5L (Euroqol 5D), Medical Outcomes Short-Form Health Questionnaire (SF-12) and Hospital Anxiety and Depression Scale (HADS)) measuring health-related quality of life, anxiety and depression were collected at enrolment and every three months. During the first wave of the UK COVID-19 pandemic (March-August 2020), approval was granted for sites to post questionnaires to participants and be returned to the sponsor, instead of collection during face-to-face study visits. Where research visits were disrupted due to the COVID-19 pandemic, but clinical visits continued, the study sponsor approved the use of information collected from clinical visits.

Outcomes

We recorded participants’ characteristics and measured feasibility, clinical, patient reported, and cost-effectiveness outcomes collected through a patient diary (Table 2). The proposed primary outcome for a definitive study will be time to confirmed remission, recorded as off-loading treatment time measured in days. Clinical outcomes were assessed to provide an initial efficacy estimate to inform the design of a definitive study. The safety of the intervention MRI was assessed.

In standard care plus , remission was defined as a temperature difference of ≤ 2⁰C between the affected and unaffected foot which was maintained or improved on two separate consecutive occasions for a period of at least four weeks(10) or at the discretion of the clinical team when temperature difference was not valid; e.g., in the presence of bilateral foot disease. This triggered a final MRI. In the intervention arm, remission was defined as an absence of sub-chondral bone marrow oedema on MRI. The clinical team will interpret the results of the MRI report to determine remission. Relapse was defined as a temperature difference of >2°C compared to the contralateral foot maintained for two or more occasions or further changes on imaging.

Table 2 - Feasibility, clinical efficacy, patient reported and cost effectiveness outcomes

Feasibility outcomes	Clinical efficacy outcomes *Collected – all study visits*	Patient reported outcomes Collected – baseline, 3 monthly until remission, then at 1 and 6-months post remission
The proportion of patients who meet the eligibility criteria	Number of new ulcerations on the index foot	Health related quality of life measured: SF-12(18) EQ-5D-5L(27), analysed using the crosswalk methodology (28)
The number of eligible patients recruited	Number of new ulcerations on the index or contralateral foot	HADS(29)
The number of participants in which an alternative diagnosis is made during the active phase of the study	Number of new infections on the index or contralateral foot	VAS
The proportion of patients that withdraw or are lost to follow up. The term ‘withdrawal’ encompasses two potential scenarios: withdrawal due to loss of consent or withdrawal due to death	Number of minor and major amputations on the index foot or contralateral at the end of the follow up phase of the study	Ability to collect resource use data - Patient Diary
		Change in employment Frequency and the amount of time participants received help with personal and household tasks Number of all healthcare appointments Number and severity of falls (Hopkins Fall Grading System)(30)
Statistical parameters of the key outcome measures to inform a sample size calculation for a definitive study	The number of participants in each arm requiring further intervention for Charcot (e.g., further immobilisation) within 6 months of remission

Abbreviations

EQ-5D-5L Euroqol 5D

HADS Hospital Anxiety and Depression Scale

SF-12 Medical Outcomes Short-Form Health Questionnaire

VAS Visual analogue scale

Statistical analysis

Descriptive statistics were used to summarise participants’ baseline characteristics and feasibility outcomes. All analyses will be conducted using a modified Intention-To-Treat approach. Whereby participants that are identified as post-randomisation exclusions (those participants who were identified as having an alternative diagnose, and therefore failed the inclusion criteria) will be excluded from the modified ITT analysis. All participants with a confirmed diagnosis will be included in the analysis. Estimates of outcome variability (e.g., standard deviation) were made with 95% confidence intervals to inform future sample size calculations. The primary efficacy outcome, ‘time in cast’, was analysed using a Cox Proportional Hazards (PH) regression model. Two baseline covariates were included in the model: 1) off-loading device, removable or non-removable; and 2) Eichenholtz classification, stage 0 or stage 1 (based on clinical and X-ray findings).

Five sites in England participated: one in the East of England, two in the East Midlands and two in Yorkshire and Humber. Participant recruitment took place between December 2017 and November 2019. Forty-three participants were randomised, 23 to intervention and 20 to standard care plus.

Participant Characteristics

Baseline characteristics were similar between the two study arms (Table 3). The mean age of participants was 59.1 (±SD11) years, of whom 29/43 (67%) were men; 34/43 (79%) had type 2 diabetes. Mean diabetes duration was 19 (±SD 11.2) years. Twenty-seven (63%) of participants reported symptoms for >1-month before a consultation with the specialist multidisciplinary foot team. Common self-reported precipitating factors were concurrent ulceration or a recent trip or fall. The most frequent site for the Charcot neuroarthropathy was the Sanders and Frykberg II (tarso-metatarsal joints). At enrolment 41/43 (95%) had an Eichenholtz Classification stage 0 or I. 21/43 (49%) participants initially received treatment with a non-removable below-knee device (Table S1).

Table 3 - Baseline participant characteristics

Baseline participant characteristics	All participants		Confirmed diagnosis of Charcot
	All randomised participants [n=43]	Confirmed diagnosis Charcot [n=30]	Standard care plus (n=16)	Intervention (n=14)
Sociodemographic
Men n [%]	29 [67%]	20 [67%]	12 [75%]	8 [57%]
Age (yrs) mean ± SD	59.1 ±11.2	59.2 ±10.8	59.2 ±9.4	51.5 ±10.8
Highest education n [%]	n=37	n=27	n=13
Left school before 16	4 [11%]	2 [7%]	1 [8%]	1 [7%]
Stayed in school until 16	11 [30%]	8 [30%]	4 [31%]	4 [29%]
Stayed in education until 18	6 [16%]	4 [15%]	3 [23%]	1 [7%]
Vocational/occupational qualification	8 [22%]	7 [30%]	2 [15%]	5 [36%]
Degree	6 [16%]	4 [15%]	2 [15%]	2 [14%]
Masters	1 [3%]	1 [4%]	1 [8%]	0
Doctorate	1 [3%]	1 [4%]	0	1 [7%]
Diabetes and diabetes related complications
Type 2 diabetes n [%]	34 [79%]	22 [73%]	12 [75%]	10 [7%]
Duration of diabetes (yrs) mean ± SD	19 ±11.2	20.5 ±11.3	24.6 ±13	15.8 ±6.7
HbA1c mmol/mol median [25th-75th IQR]	69 IQR 57-87	77.5 IQR 60-96	73.5 IQR 61-84	77.5 IQR 59-99
eGFR <60 n [%]	13 [30%]	9 [30%]	3 [19%]	6 [43%]
Type 1 BMI mean ± SD	30.9 ±6.3	32.1 ±SD 5.4	33.8 ±5.9	30.6 ± 5.1
Type 2 BMI mean ± SD	32.5±SD 7.0	32.1 ±SD 6.5	32.2 ±7.7	32.2 ±5.2
Cerebrovascular events n [%]	4 [9%]	2 [7%]	1 [6%]	1 [7%]
Cardiovascular events n [%]	10 [23%]	6 [20%]	2 [13%]	4 [29%]
Nephropathy n [%]	11 [26%]	9 [30%]	2 [13%]	7 [50%]
Retinopathy n [%]	18 [42%]	14 [47%]	10 [63%]	4 [29%]
Palpation foot pulses n [%]
No foot pulses palpable	4 [9%]	3 [10%]	1 [6%]	2 [14%]
One-foot pulse palpable	1 [2%]	0	0	0
Two-foot pulses palpable	38 [88%]	27 [90%]	15 [94%]	12 [86%]
Ankle Brachial Index n [%]	n=41	n=28	n=15	n=12
Ankle Brachial Index 0.5-0.79	1 [2%]	1 [4%]	1 [4%]	0
Ankle Brachial Index 0.8-0.99	4 [10%]	3 [11%]	0	3 [25%]
Ankle Brachial Index 1.0-1.4	31 [76%]	22 [79%]	13 [81%]	9 [75%]1
Ankle Brachial Index >1.4	5 [12%]	2 [7%]	2 [13%]	0
Monofilament perception n [%]
-ve at 3/3 sites	33 [77%]	24 [80%]	13 [81%]	11 [79%]
-ve at 2/3 sites	4 [9%]	0	0	0
-ve at 1/3 sites	1 [2%]	2 [7 %]	1 [6%]	1 [7%]
+ve at all sites n [%]	5 [12%]	4 [13%]	2 [13%]	2 [14%]
Mean vibration perception at hallux	n=29	n=22	n=11	n=11
Hallux (≥25volts)	23 [79%]	19 [86%]	10 [91%]	9 [82%]
Previous or current foot complications n [%]
Previous minor amputation index foot	7 [16%]	5 [17%]	4 [25%]	1 [7%]
Previous minor amputation contralateral foot	5 [12%]	4 [13%]	3 [19%]	1 [7%]
History of previous Charcot either foot	6 [14%]	6 [20%]	3 [19%]	3 [21%]
Ulceration at enrolment on index foot	12 [30%]	7 [23%]	5 [31%]	2 [14%]
Ulceration at enrolment on contralateral foot	1 [2%]	0	0	0

Abbreviations

BMI Body mass index

eGFR Estimated Glomerular Filtration rate, ml/min

HbA1c Glycated haemoglobin (A1c), mmol/mol

Feasibility Outcomes

Eligibility

Participants were approached during routine foot clinic visits. 64/105 (61%) potential participants met the eligibility criteria. Nine participants had multiple reasons for exclusion (Table S2). The main reason was a history of Charcot neuroarthropathy within the last six months. Of the potentially eligible participants 43/64 (67%) agreed to study participation.

Participant retention

Figure 1 shows the CONSORT diagram. 30/43 (70%) participants received a confirmed Charcot neuroarthropathy diagnosis, the remaining 13 (30%) exited the study due to an alternative diagnosis (3 stress fracture, 2 osteoarthritis, 2 infection, 1 soft tissue injury, 5 not reported). Of the 30 participants with a confirmed Charcot neuroarthropathy diagnosis, 19 (63%) went into remission, and 5 were lost to follow-up (2 relocated, 2 due to COVID-19 and 1 unknown).Six (20.0%) did not achieve remission at the end of the 12-month active phase. They did not progress into the follow-up phase but were included in analyses. During the six-month follow-up phase, two participants experienced a relapse, one in each study arm.

^*Participants transferred from the active phase to the follow-up phase of the study once the Charcot neuroarthropathy was assessed as in remission. Therefore, the total number of participants decreases over the 12-month active phase. Only participants who achieved remission within the 12-month active phase of the study entered the follow-up phase of the study.

Adherence to study procedures

During the active phase, 469/497 (94%) of visits not disrupted by COVID-19 pandemic were completed. 438/497 (88%) of study visits were completed in the one-week timeframe window (Table S3). 79 visits were partially or completely disrupted by COVID-19.

For participants with a confirmed Charcot neuroarthropathy diagnosis, 26/31 (84%) of MRIs that were not disrupted by COVID-19 pandemic were completed. It is not known why the remaining five did not go ahead. A further twelve were missed due to changed research radiology priorities during COVID-19 pandemic (Table S4). Of the MRIs that went ahead, 16/26 (62%) were undertaken within the two-week window; the median time for the remaining ten was 20 days either side of the 14-day window (range -30 to +48 days). Nine non-study MRIs were completed in each study arm; no data are available on which foot they concerned.

Clinical and safety outcomes

All 30 participants with a confirmed diagnosis of CN were included in the Cox regression analysis hazard model. In this feasibility study there was no statistical difference in the time in off-loading device between the two arms of the study: Hazard Ratio (HR) 0.405 (95% CI 0.140-1.172), p=0.096 (Table 4). As this was a feasibility study it was not designed to test the effectiveness of serial MRI in diagnosing remission. The time in off-loading device was 235 (±108.3) days for the standard care plus arm compared to 292 (±177.4) days for the intervention arm. Time in off-loading device will be the proposed primary outcome in a future trial. Participants who were provided with a non-removable device went into remission sooner than those treated with a removable device: HR 0.285 (95% CI 0.107-0.758), p=0.012. The Eichenholtz classification at baseline did not affect time to healing: HR 1.083 (95% CI 0.349-3.362), p=0.890.

Table 4 – Results from Cox regression analysis on time in cast (days)

Enrolment n=30	Covariates	Time in cast (days)		P-value	Hazard Ratio	95.0% Confidence Interval
		Mean	SD			Lower	Upper
Randomisation arm	Intervention	292.6	±108.3	0.096	0.405	0.140	1.172
	Standard care plus	235.2	±117.4
Off-loading device	Non-removable	198.6	±117.8	0.012	0.285	0.107	0.758
	Removable	325.3	±70.3
Eichenholtz stage	Stage 0	267.5	±108.5	0.890	1.083	0.349	3.362
	Stage I	252.4	±130.4

One participant in the standard care plus arm was admitted to hospital because of foot complications; no minor or major amputations were reported. Thirty-eight ulcerations were recorded on 19 participants during the active phase, of which 12 were attributed to the off-loading device. Participants reported 84 falls, six required outpatient medical attention, and a further four hospital admissions. No adverse events associated with the intervention (MRI scans) were reported.

Patient reported outcomes

For the visits that were conducted face-to-face, completion rate of patient-reported outcome measures were between 71-100% (Table S5 and S6). Half of the participants reported anxiety and depression scores higher than normal levels. The majority of participants scored (well) below normal levels for the physical component score, and just under half scored (well) below normal for the mental component score (18). Nearly all participants reported pain and problems with mobility and completing usual activities. The EQ-5D index calculated using the crosswalk mechanism and self-rated health status was lower than that for aged-matched population normals (19).

Patient diary and cost-effectiveness analysis

A number of data points in the patient diary were not completed, and in places we were unable to distinguish between truly missing data or zero values that were not reported. Five participants reported job changes during the study. During the active phase, participants reported a mean of 18.4 visits per participant. 62% of appointments concerned the foot. Nineteen participants reported they needed help on 599 occasions ranging from 5-900 minutes per week. Common tasks requiring help were shopping, cleaning, and bathing.

This feasibility study recruited 43 participants with a suspected or confirmed Charcot neuroarthropathy diagnosis. Despite not achieving the recruitment target of 60 participants, and study interruptions due to the COVID-19 pandemic, our sample size was sufficiently large enough to draw conclusions about the feasibility and a definitive trial.

Our participants were representative of the wider Charcot neuroarthropathy population, with more men , being in their fifth decade, and diabetes duration >ten years(20). In this study the most common site for the Charcot neuroarthropathy was Sanders and Frykberg II (tarsometatarsal joints), this is consistent with other studies(4). The main reason for ineligibility was a previous Charcot neuroarthropathy within the last six months. We argue that it is not possible to reduce this as it may affect the results with the inclusion of relapsed Charcot neuroarthropathy , which may have different healing times to new cases.

Two-thirds of eligible participants agreed to take part. We recruited similar participant numbers to observational studies on monitoring techniques(6,12,21) and recent randomised controlled trials on pharmacological treatment of Charcot neuroarthropathy (22,23). More participants than anticipated were withdrawn from our study due to an alternative diagnosis. This reflects the difficulty in diagnosing Charcot neuroarthropathy at Eichenholtz stage 0. During the active phase the attrition rate was 12% which is within acceptable limits and does not affect the results of this study(24).

Two-thirds of participants had an Eichenholtz Classification stage 0 at baseline with no changes on X-ray. This highlights the need to use MRI as an adjunct to X-rays in Charcot neuroarthropathy diagnosis and monitoring. Excluding the effect of COVID-19 pandemic on MRIs, 84% intervention MRIs were completed, and no safety incidents reported. This supports the feasibility, safety, and participants’ acceptability of serial MRIs.

During the first wave of the UK COVID-19 pandemic, some hospitals involved in the study stopped or restricted research radiology imaging, reducing the number of completed study MRIs. This may have resulted in either an underestimation or overestimation of the ‘time in cast’.

Participants experienced multiple episodes of concurrent ulceration and infection. This highlights the previously recognised limitations of using infra-red thermography to monitor Charcot neuroarthropathy . If similar findings were replicated in a definitive trial this further justifies the need to use MRI as a monitoring technique for Charcot neuroarthropathy .

The non-study MRIs that were completed may be contamination, diluting the relationship between intervention and outcome. We do not know whether these MRIs reflected a change in practice due to study participation.

Our participants were considered a ‘clinically vulnerable’ group and advised by the UK government to only attend essential clinical visits which excluded study visits. Consequently, the end point ‘time in cast’ and other outcomes were not always collected. Some clinical teams transferred participants from non-removable to removable offloading devices to reduce the number of follow-up appointments. Wearing removable devices is associated with increased time to remission(4). This may have increased the end point ‘time in cast’. We do not have data on whether the two arms of the study were equally affected by this.

The results related to patient-reported outcomes need to be interpreted with caution: this is a feasibility study not powered to detect between-group or longitudinal differences. We showed that receiving treatment for Charcot neuroarthropathy has physical, emotional, and socioeconomic ramifications and are results are consistent with others(25). The minimum clinically important difference for EQ-5D has been estimated to be 0.03(26). The increase in EQ-5D scores observed (table S4) shows that using serial MRI to diagnose Charcot neuroarthropathy remission has potential to be cost-effective. We also showed the important and unrecognised burden of informal care for people with Charcot neuroarthropathy . In a definitive study we will seek to capture the cost of this informal care and include this in a cost effectiveness analysis.

Strengths and limitations

The strength of this study is the recruitment of study participants who are representative of the wider population of people living with Charcot neuroarthropathy . The COVID-19 pandemic reduced data and intervention completeness and the clinical and patient reported outcomes that were collected.

Implications for a definitive study

A definitive study on serial MRI in people with Charcot neuroarthropathy attending multidisciplinary foot clinics is justified and feasible, based on recruitment and retention rates, and acceptability of the intervention and study visit schedule to participants.

In a future study randomisation should be stratified for the type of off-loading device. Normal plain X-rays, widespread inflammation, and participants awaiting their baseline MRI meant that it was sometimes difficult for investigators to classify the location of the Charcot neuroarthropathy at baseline and this led to some missing data. To address this missing data we will modify the data collection tool to ask investigators to confirm or record the location of the Charcot neuroarthropathy at baseline and the three month follow-up visit. We found low levels of data completeness in the patient diary. Therefore, in a future study we will modify the patient diary and collect a more complete picture of participants’ costs. The diary will be co-produced with PPI to ensure the diary is relevant to and reflects the priorities of people with CN and other key stakeholders.

Prior to any future definitive trial, we will undertake a Delphi consensus study to optimise and standardise the intervention serial MRI. Finally, we will seek to capture the reasons for the non-study MRIs.

A continuation of the COVID-19 pandemic or another pandemic may disrupt a future study. To prepare for the possibility of this we will seek to maximise data collection through additional participant reported outcomes. This could include the type of off-loading device being used, self-monitored foot temperatures, and outcomes such as ulceration and infection.

This study has shown that it is justified and feasible to carry out a fully powered definitive study to evaluate the effectiveness of MRI in disease monitoring in Charcot neuroarthropathy .

ABPI Ankle brachial pressure index

BMI Body mass index

CI Confidence Interval

CN Charcot neuroarthropathy

eGFR Estimated Glomerular Filtration rate, ml/min

EQ-5D-5L Euroqol 5D

F Follow up visit

FU Follow up phase

HADS Hospital Anxiety and Depression Scale

HbA1c Glycated haemoglobin (A1c), mmol/mol

HR Hazard Ratio

MRI Magnetic Resonance Imaging

NHS National Health Service

R Remission

SD Standard deviation

SF-12 Medical Outcomes Short-Form Health Questionnaire

VAS Visual analogue scale

WHO World Health Organisation

Ethical approval and consent to participate

The study has been reviewed by East Midlands - Derby Research Ethics Committee, 04/10/2017, ref: 17/EM/0288. The study is registered on the ISRCTN registry: reference number ISRCTN74101606. All participants provided written consent to take part in the feasibility study.

Consent for publication

Not applicable

Availability of data and materials

The datasets generated and/or analysed during the current study will be available from the corresponding author on reasonable request, provided appropriate credit is attributed to the original authors and the data source.

Competing interests

The investigators have no financial or other competing interests that impact on their responsibilities towards the scientific value or potential publishing activities associated with the study.

Funding

Catherine Gooday, Clinical Doctoral Research Fellow (ICA-CDRF-2015-01-050) is funded by Health Education England (HEE) / National Institute for Health Research (NIHR) for this research project. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.

Author’s contributions

The authors thank the participants and the staff at all study sites. CG is the National Institute for Health Research (NIHR) Clinical Doctoral Fellow and Chief Investigator. CG and FG developed the initial idea for the study. FG, WH, FP, JW, ES and KD made substantial contributions to the conception and design of the study. CG led the study, data analysis and interpretation. CG drafted the manuscript. All authors critically reviewed and revised the manuscript for important intellectual content. ES provided clinical trial operations and quality assurance expertise, LS provided statistical expertise, and GB provided health economics expertise. All authors read, amended, and approved the final manuscript.

Acknowledgements

We are very grateful to the staff and participants at the trial centres. The trial was conducted in collaboration with Norwich CTU whose staff supported the design, conduct and analysis of the trial, including the data management team Antony Colles & Maria Leathersich. We thank Ms Sarah Doyle, Research Administrator for her support with study management. This study is sponsored by the Norfolk & Norwich University Hospitals NHS Trust ([email protected]).

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A randomised feasibility study of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes (CADOM)

Status:

Journal Publication

Version 1

Abstract

Figures

Novelty Statement/what’s New

Background

Methods

Participants – Inclusion and exclusion criteria

Randomisation, blinding and data collection

Sample size

Study Interventions

Study procedures

Outcomes

Statistical analysis

Results

Participant Characteristics

Feasibility Outcomes

Eligibility

Participant retention

Adherence to study procedures

Clinical and safety outcomes

Patient reported outcomes

Patient diary and cost-effectiveness analysis

Discussion

Strengths and limitations

Implications for a definitive study

Conclusion

Abbreviations

Declarations

Ethical approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Author’s contributions

Acknowledgements

References

Status:

Journal Publication

Version 1