Sealed Therapeutic Shoe vs. Total Contact Cast as Treatment of Diabetic Foot Ulcers: a Multicenter RCT
Phase: NA
Conditions: Diabetic Foot
Sponsor: Region Örebro County

Study protocol 
 
Sealed Therapeutic Shoe vs. Total Contact Cast as Treatment of Diabetic 
Foot Ulcers: a Multicenter RCT   
 
Clinical Trial Registration Number:  Unique Protocol ID: 18RS6667 
 
Date: 9 September 2019 
 
 
 
 

Background 
Approximately 19-34 % of all people with diabetes will at some time in life develop a 
diabetic foot ulcer (DFU).1 People with diabetes are especially prone to develop foot ulcers 
because of different diabetic complications, especially angiopathy and peripheral neuropathy.  
The DFUs are often hard to heal and the treatment is long-lasting. The DFUs result in lower 
physical and mental quality of life and affects social relationships.2 The treatment is also very 
costly,1, 3 it has been estimated that 25-50 % of diabetic inpatient care is related to DFUs.4 
Despite extensive treatment, all DFUs do not heal but some end in amputation. People with 
diabetes are at a 25-fold risk of amputation and every 20 second a person somewhere in the 
world has the foot amputated because of diabetes.5 85 % of these amputations are preceded by 
a foot ulcer6 and many of these ulcers and amputation could have been prevented.7  
 
Total contact cast (TCC) as gold standard treatment of DFUs 
Plantar DFUs often are the result of a combination of foot deformities that increase plantar 
pressures when the person walks and that the person keeps walking despite high pressure and 
ulcers because he or she has lost sensation in the feet because of sensory neuropathy. 
Literature reviews and international guidelines8, 9 recommend non-removable knee-high 
offloading devices, for example, a total contact cast (TCC) to treat plantar DFUs, as this 
offloads the ulcer from mechanical loading all day and night. Still, TCC is not accepted by all 
patients and is contraindicated in a number of cases because of negative side-effects. Most of 
these side-effects are the consequences of immobilizing the ankle joint, which impairs gait 
and results in lower ambulatory activity. For example, side-effects include reduction of joint 
flexibility, weight gain, muscle atrophy, sick leave from work and social isolation.10 In 
addition, a TCC can give secondary ulcers why weekly visits to the hospital is necessary to 
change casts. For these reasons, TCC is only used for a minority of the patients for whom it 
could be beneficial, despite being the gold standard treatment.11  
 
For working patients, casting often means sick leave from work, but casting can also be 
difficult for older patients with impairments of gait and balance. For patients where TCC is 
contraindicated or not tolerated, guidelines recommend removable offloading devices despite 
it is well known that these devices are not very effective.8 In practice, this means that many 
patients do not receive effective treatment. Another problem is that many patients get new 
foot ulcers after treatment with TCC,12 in part because adherence to using therapeutic 
footwear after healing is lower than desirable.13 
 
Sealed therapeutic shoe as alternative treatment  
The investigators have developed a new treatment concept, sealed therapeutic shoe, which 
potentially can fill the need for effective ulcer treatment without limiting ambulatory activity 
with its associated negative consequences for physical, mental and social health, and to a 
lower cost, resulting in fewer obstacles for clinical use. 

The concepts include therapeutic shoes with custom-made insoles, where the new part is how 
the insole is optimized to offload the ulcer from mechanical loading and that the shoe is 
”sealed” with a soft plastic strap and is used day and night, like a cast, and is only removed 
when changing the ulcer dressings. The ulcer is thereby offloaded but the person is free to 
ambulate and work as usual, and no cast changes are necessary. In addition to effective ulcer 
treatment and fewer side-effects the investigators hope that the positive experience of that 
high adherence to using therapeutic shoes results in healing will lead to higher adherence after 
healing, and thereby reduction of the risk of ulcer recurrences in the future.  
The method to offload foot ulcers was first tested in a case-study, where it was found that the 
shoe and insole effectively offloaded the ulcer.14 After this the investigators evaluated the 
whole sealed shoe concept in a feasibility study on seven people with DFU. All ulcers healed 
and complications were few.17 The investigators are now going to evaluate the effects of 
sealed therapeutic shoes compared to gold standard treatment, that is, TCC.  
Aims 
 
 
The overarching aim is to evaluate whether sealed shoe can heal DFU at least as effectively as 
TCC, but with fewer adverse events during the treatment period, better long-term effects and 
to a lower cost.  
Specific aims 
Aim 1. To investigate whether a sealed shoe can heal DFUs at least as effectively as TCC.  
Aim 2. To investigate whether there is a difference in adverse events during the treatment 
period with sealed shoe and TCC.  
Aim 3. To investigate whether there is a difference in long-term effects (up to 12 months after 
end of treatment) with sealed shoe and TCC.  
Aim 4. To investigate whether there is a difference in health economic outcomes between 
treatment with sealed shoe and TCC.  
The null hypothesis is that a sealed therapeutic shoe does not heal DFUs at effectively as 
TCC, and that there are no differences between sealed shoe and TCC in adverse events, long-
term effects and health economic outcomes.  
 
Methods 
The study is a non-inferiority multicenter randomized controlled trial (RCT). 
Participants 
Inclusion criteria: at least 18 years old, diagnosed diabetes mellitus (all types) and foot ulcer 
under metatarsal heads. A foot ulcer is here defined as “a break of the skin of the foot that 
includes minimally the epidermis and part of the dermis.”15 
Exclusion criteria: large ulcers (covering 3-5 metatarsal heads), toe pressure or TcPO2 <30 
mmHg, infection of IWGDF grade 3 (if uncontrolled or treatment has not been administered) 
or IWGDF grade 4, life expectancy <1 year, active Charcot foot, need of custom-made shoe, 

and inability to read or write Swedish. In addition, people will be excluded where dementia, 
language- or other communication difficulties, active alcohol or substance abuse, or other 
factors increase the risk that adverse events will not be noted or reported, if the person does 
not have adequate social support.  
The study is a randomized controlled non-inferiority trial where it will be investigated 
whether a new intervention (sealed shoe) is at least as effective as the established intervention 
(TCC).  
Primary outcome is proportion of healed ulcers after 12 weeks of treatment. Based on the 
literature and our feasibility study the proportion of healed ulcers after 12 weeks treatment is 
estimated to 90% with sealed shoe or cast.16, 17 If accepting p=0.05, a statistical power of 80% 
and a non-inferiority limit of 10%, 112 participants are needed. To compensate for attrition of 
participants, the aim is to recruite 150 participants. However, if it turns out that it is too 
difficult to recruit 150 participants, the recruitment of participant will end when the primary 
end point (healing at 12 weeks) has been observed for 56 participants per group, giving a total 
of 112 which fulfills the sample size calculation. 
The participants will be randomized to treatment with sealed therapeutic shoe or TCC. The 
randomization will be stratified for ulcer size (smaller or bigger than 1 cm2, ulcer size 
calculated as longest diameter*longest perpendicular diameter) and study center, and use 
random permuted blocks of randomly varying size. 
 
Recruitment of participants 
People who fulfill the inclusion criteria and not the exclusion criteria will be given oral and 
written study information and asked about whether they are interested in participating in the 
study. Those who agree will sign an informed constant to participate.  
Intervention group, sealed therapeutic shoe: A prosthetist/orthotist will try out new 
therapeutic shoes to the participants and make individual insoles after casts of the feet. There 
will a limited number of shoe types to choose between and the procedure and material for the 
insole production will be standardized. The ulcer will be offloaded by adjusting the insoles 
with the help of plantar pressure measurement using the F-scan system (Tekscan, Boston, 
MA, USA). The “seal” of the shoe consists of a soft plastic strip (Bracelok, DJO Nordic, 
Malmö) that have to be broken to remove the shoe.  
Control group, TCC: The participants will be treated with TCC, applied in a standardized 
manner. Participants in this group will also receive shoes and insoles, according to the same 
protocol as above, before TCC treatment is initiated to be comparable to the other group in the 
long-term follow-up after healing, when both groups will use shoes and insoles to prevent 
reulceration.  
Both groups will visit the cast technician 1-2 times/per week depending on the status of the 
ulcer. The cast technician will change dressings, note whether the seal has been broken (for 
the intervention group), change casts (for the control group), photograph and document ulcers 
and complications, and ask participants if they have experienced any issues with the 
treatment. After this, a new dressing is applied, and the shoe is sealed (intervention group) or 

a new cast is applied (control group). Participants will use a cover on the shoe or cast while 
taking a shower, and for the intervention group a cover will also be used when sleeping. Both 
groups will receive written information about potential complications and contact information 
to the clinics.  
Data collection 
Participants in both groups will be assessed by a physiotherapist on five occasions (Figure 1): 
at base-line, four weeks into the treatment period, and then 1, 6 and 12 months after healing 
(when treatment is ended). For the 4 week into treatment and 1 month post-treatment 
assessments, a visit window of ±1 week will be used. For the 6 and 12 months post-treatment 
assessments, a visit window of ±1 month will be used. Standardized and validated instruments 
and assessment methods will be used for the data collection (Table 1).  
 
 
Aim 1: Ulcer healing (primary end point) 
Primary outcome measure is ulcer healing after 12 weeks of treatment, defined by the Food 
and Drug Administration (FDA) as full skin epithelization of the ulcer, confirmed by a second 
observation 14 days later.18 The cast technicians will assess ulcer healing in both the 
intervention group and control group. They will also photograph the ulcer and healed skin so 
a person blinded to group allocation can assess ulcer healing afterwards.   
Aim 2: Adverse events during treatment (secondary end points) 
Adverse events that are judged to be related to the offloading devices (shoe or TCC) will be 
classified as adverse device effects (ADE) and serious adverse device effects (SADE).32 ADE 
include, but are not limited to, skin abrasions, blisters, sleep disturbances, issues with gait and 
balance, etc. SADE include, but are not limited to, new foot ulcers that result in amputation 
(major amputation = above ankle, minor amputation = below ankle), sepsis, etc.  
Averse events that are not related to the offloading devices are classified as adverse events 
(AE) and serious adverse events (SAE).32 AE include, but are not limited to, skin abrasions, 
new foot ulcers on the contralateral foot and not related to the device, etc. SAE include, but 
are not limited to, death, amputation, onset of acute Charcot foot, sepsis, etc. (not related to 
the offloading device). However, in accordance with previous studies on this patient 
population, the investiagators choose not to include all AE and SAE as the patient population 
suffers from multiple co-morbidities and therefore a high incidence of illness and hospital 
admissions unrelated to the DFU and offloading devices can be expected.33  Therefore, all 
Randomization 
(n=150) 
TCC 
Sealed shoe 
Assessment occasions 
Base-    4 weeks  1mth post   6mths    12mths 
  line                        treatm.       
Figure 1. Participants and assessment 

ADE and SADE will be assessed, but only certain types of AE and SAE that are of particular 
interest, such as, amputation, death and onset of acute Charcot foot.  
ADE, SADE, AE and SAE will be assessed with the aid of questionnaires, case report form 
(CRF), photographs of ulcer and skin, and patient files.   
Aim 3: Long-term effects (secondary end points) 
The secondary endpoints are time to healing and measures listed in Table 1. Each secondary 
endpoint is measured between one and five occasions during the study. For example, 
incidence of new foot ulcers, amputation, onset of acute Charcot-foot, death, adherence to 
using therapeutic shoes and locus of control will be assessed.  Our hope is that the positive 
experience in the intervention group of that using therapeutic shoes can heal ulcers will result 
in a stronger internal locus of control and higher adherence to using therapeutic shoes after 
healing, so that fewer people will reulcerate or be affected by foot complications in the long 
term.   
Data from patient files, questionnaires and the physiotherapists’ assessments will be used for 
the analysis.  
Aim 4: Health-economic outcomes (secondary end points) 
The questionnaires RAND-36 and EQ-5D-5L will be used to assess general quality of life. 
Data from patient journals, Swedish Social Insurance Agency’s system, and self-report 
questionnaires will be used to assess health care consumption and other costs.   
 
Statistical analysis  
See separate document for statistical analysis plan. 
 
Research ethics 
The participants will be informed about risks of the interventions in the written information 
that also will include contact information for the clinics. Risks will be minimized by 
excluding certain patient groups with heightened risks of side-effects not being noted or 
reported, and by a frequent follow-up during the intervention period. The study has been 
approved by the region ethics review board in Uppsala, Sweden (documents 2018/387 and 
2019-03512).  
 
 
 
 

Table 1. Overview of variables and assessment methods.  
Variable 
Assessment method  
Assessment occasion 
Specific 
aim 
 
 
Treatment 
period 
Follow-up after treatment 
end 
 
 
Base-  
line 
4 
weeks 
1 
month 
6 
months 
12  
months 
Ulcer healing 
Clinical observation + 
blinded photo assessment 
X 
X 
X 
 
1 
Skin complications 
Clinical observation + 
blinded photo assessment 
X 
X 
X 
 
2 
Glycemic control 
Blood sample (HbA1c) a 
X 
X 
X 
X 
X 
2,3 
BMI  
Measurement of weight and 
height  
X 
X 
X 
X 
X 
2,3 
Gait function  
10 meter walk testb 19 
X 
X 
X 
X 
X 
2,3 
Gait function 
Timed up and gob 20  
X 
X 
X 
X 
X 
2,3 
Balance 
Berg balance scaleb 21 
X 
X 
X 
X 
X 
2,3 
Muscle atrophy  
Calf circumferencea 22 
X 
X 
X 
X 
X 
2,3 
General quality of life 
RAND-36c 23,EQ-5D-5Lc 24  
X 
X 
X 
X 
X 
2,3,4 
Disease-specific  
quality of life 
DFS-SFc 25 
X 
X 
X 
X 
X 
2 
Physical activity  
ActivPALd 26  
X 
X 
X 
X 
X 
2,3 
Physical activity 
National Board of Health 
and Welfare’s indicator 
questions27 
X 
X 
X 
X 
X 
2,3 
Bone mass density  
DXAe (heel bone)  
X 
 
X 
X 
X 
2,3 
Locus of control 
Questions from MHLC-Cc 28  
X 
 
X 
X 
X 
2,3 
Ankle range of 
motion 
Goniometer a 29 
X 
 
X 
X 
X 
2,3 
Ankle strength 
Dynamometer a 30 
X 
 
X 
X 
X 
2,3 
Adherence to 
therapeutic shoes 
Questions from Q-TFA c 31 
X 
 
X 
X 
X 
3 
Treatment satisfaction Visual analogue scalec 
 
X 
X 
 
 
2 
New ulcers, 
amputations, death, 
Charcot foot 
Patient file and self-report c 
 
 
 
X 
X 
3 
Health care 
consumption 
Patient administration 
systems and self-reportc 
 
 
X 
X 
X 
4 
Sick leave from work 
Self-report,c Swedish Social 
Insurance Agency’s system 
 
 
X 
X 
X 
4 
aStandardized method,  bfunction test, cquestionnaire, dactivity monitor,  eDual-energy X-ray absorptiometry 

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