3C Patch for treating diabetic foot ulcers

The main clinical evidence comprises 4 studies, 1 of which is a randomised controlled trial

3.1 The EAC assessed 4 studies including 332 people with diabetic foot ulcers (DFUs). One study was a randomised controlled trial (RCT; n=266) and 3 were case series, 1 of which was published as an abstract (the case series included 44, 5 and 17 people). Two further studies identified by the company were not included by the EAC because these were not relevant to the decision problem. For full details of the clinical evidence, see section 3 of the assessment report.

The RCT was well conducted but some aspects of the design do not reflect NHS practice

3.2 The Game et al. (2018) RCT was considered to provide the best available data on the use of 3C Patch in relation to the decision problem. This was because it is a UK-based RCT that included people whose ulcers had a less than 50% reduction in area after 4 weeks of standard care (described as 'hard-to-heal' ulcers by the study authors). The trial also measured clinically relevant outcomes and the EAC judged it to have a low risk of bias. However, the EAC noted some issues with the external validity of the trial. Expert advice indicated that, following the publication of NICE guidance in 2019, UrgoStart has become the standard of care. As the Game et al. (2018) study took place between 2013 and 2017, only 1 person received UrgoStart in the run-in period, although other protease modulating dressings were used by 40% of people during the run-in. Entry into the treatment phase of the trial was determined by a decision rule (failure to respond to standard care provided in the run-in period, based on a reduction of less than 50% in ulcer area). Clinical experts stated that this rule is not routinely used in practice to judge response to treatment. It is also unlikely to be readily implementable across different settings because accurate ulcer-area measuring tools are not widely available in the NHS. Also, other factors may be used in clinical practice to assess treatment response and eligibility for 3C Patch, such as lack of ulcer offloading, infection status or poor blood supply. Clinical experts also had different opinions on whether 3C Patch would be continued if there was a moderate or severe ulcer infection. The EAC noted that 3C Patch treatment was continued while ulcers were infected in the Game et al. (2018) trial. The EAC concluded that although the trial was well conducted, some of the aspects of the study design may not be reflective of NHS practice.

The company's proposed stopping rule was not used in the RCT

3.3 The EAC noted the way the intervention was delivered in the trial did not align to the company's proposed treatment pathway. The company stated that 3C Patch use should be reviewed after 4 to 6 weeks and stopped if there has not been a 50% reduction in ulcer area. This stopping rule was not followed in the clinical trial because everyone in the treatment group had 3C Patch until healing or up to 20 weeks. The EAC considered this an important limitation of the evidence base.

3C Patch increases the proportion of people with complete epithelialization or healing at 20 weeks in the trial population

3.4 RCT evidence (Game et al. 2018) found that 34% of ulcers (45 out of 132) in the intervention group had complete epithelialization or healing at 20 weeks compared with 22% (29 out of 137) in the standard care group (odds ratio 1.58; 95% confidence interval [CI] 1.04 to 2.40; p=0.0235). In the case series, healing rates at 20 weeks were 52% (23 people out of 44) and 61.9% (13 ulcers out of 21; Löndahl et al. 2015 and Katzman et al. 2014, respectively).

3C Patch reduced time to healing and ulcer area at 20 weeks in the trial population

3.5 RCT evidence (Game et al. 2018) found that 3C Patch reduced time to healing compared with standard care over 20 weeks (hazard ratio 1.709; 95% CI 1.071 to 2.728; p=0.0246). In the subgroup that had healed at 20 weeks, the median time to healing was 72 days (interquartile range [IQR] 56 to 103) in the 3C Patch group compared with 84 days (IQR 64 to 98) in the standard care group (difference 12 days; p=0.0343). This study also found a statistically significant decrease in ulcer area over a 20-week period in the 3C Patch group (p=0.0168).

Evidence does not support 3C Patch reducing the risk of amputation or ulcer infection and direct clinical evidence for the other company-claimed benefits is limited

3.6 Game et al. (2018) found no significant difference in those with a new infection within 20 weeks, visits reporting infection (as a proportion of total visits) or total days of antibiotic therapy. The study also found no significant difference in new minor or major amputations affecting the index or contralateral limb. However, the study was not powered to detect differences in these parameters. The EAC further noted that there was insufficient direct trial evidence to support claimed benefits around reducing demand for ulcer care and reducing follow-on treatments. Any improvement in quality of life was uncertain as these measures were only reported in an abstract for a small subgroup of people (10 people in the 3C Patch group and 8 people in the standard care group, all with ulcers extending into tendons; Löndahl et al. 2019).

The company's cost model uses a Markov model comparing 3C Patch with standard care in those with hard-to-heal DFUs

3.7 A Markov model was used to estimate costs and quality-adjusted life years associated with the use of 3C Patch with standard care compared with standard care alone. It took into account the impact of each treatment option on the likelihood of healing, re-ulceration, major amputation, minor amputation and death over a 2-year time horizon. The population included in the model were those with hard-to-heal DFUs, which aligned with the population included in Game et al. (2018). For full details of the cost evidence, see section 4 of the assessment report.

The company's cost model uses a stopping rule for 3C Patch treatment and makes use of data from an unplanned post-hoc analysis of the trial

3.8 The company's model included a number of assumptions that reflect the company's proposed use of 3C Patch within the DFU treatment pathway. It incorporated an assumption that 3C Patch use would be stopped if an ulcer has not reduced in area by 50% or more within 5 weeks of treatment. This stopping rule was not used in the Game et al. (2018) trial, so the company conducted an unplanned post-hoc analysis of the trial data to generate the following clinical inputs:

The company's model structure is appropriate but does not account for 3C Patch discontinuation due to infection

3.9 The EAC judged the overall model structure and time horizon to be appropriate. However, it identified some errors in the company costing and disagreed with some of the key clinical and cost parameters used in the company's model (see sections 3.10 to 3.13). Additionally, in light of the varying clinical expert views on whether 3C Patch use should continue when an ulcer is infected (see section 3.2), the EAC created a second model that added a 'moderate or severe' infection state. In this state, people with a moderate or severe infection stop using 3C Patch until their ulcer is no longer infected.

The EAC revised 3C Patch discontinuation rates in the model

3.11 As noted in section 3.7, the company model included a stopping rule applied in the 3C Patch arm, which was implemented at week 5. The EAC noted that in Game et al. (2018) everyone in the treatment arm continued 3C Patch use until healing or up to 20 weeks. It also noted that clinical experts stated that the stopping rule used in the company model was unlikely to be implemented in clinical practice. This is because accurately measuring ulcer size would need specialist equipment and 3C Patch treatment would likely continue if any significant improvement in ulcer size is seen when compared with previous treatments. Therefore, the EAC changed the discontinuation rate to 0% (meaning everyone in the treatment arm would continue 3C Patch until healing or for 20 weeks).

The EAC revised the healing rates in the model in line with published RCT data and its preferred discontinuation rates

3.12 As noted in section 3.7, the healing rates in the company's model were based on an unplanned post-hoc analysis of the Game et al. (2018) trial data. The EAC revised these parameters in their model to reflect the healing and discontinuation rates seen in the intention to treat population published in the RCT (Game et al. 2018). This was because the post-hoc analysis excluded a substantial amount of the data, particularly for healing at 6 to 20 weeks in the 3C Patch arm. This increased uncertainty in the probabilities of healing used in the model. This was important because the probability of healing with 3C Patch in weeks 6 to 20 was a key driver in the company model and a small reduction in healing rate (around 0.6%) changed the direction of the company's cost case.

The EAC made a number of amendments to the costs used in the base case model

3.13 The EAC made a number of amendments to the costs in the base case model including using resource use data, where possible, from an unpublished economic analysis of the Game et al. (2018) RCT (Farr et al., unpublished). The EAC changes to cost inputs, as well as the corrections made to cost errors, resulted in almost all costs in the EAC model being updated. These included changing dressing costs from BNF to supply chain, adjusting number and length of outpatient visits and adjusting the proportion of people having inpatient procedures.

The EAC's base case suggests that 3C Patch is cost incurring compared with current care

3.14 The company's base case results showed cost savings of £191 per person over 2 years when 3C Patch is used instead of standard care. But, the EAC's base case results found that 3C Patch is cost incurring compared with standard care. The incurred costs were £1,590 per person over 2 years when modelled without an infection state (model A) and £1,993 when modelled with an infection state (model B).

The EAC's sensitivity analysis found the cost of index ulcers and discontinuation rate to be the biggest cost drivers

3.15 The EAC's sensitivity analysis found that the biggest cost drivers in the economic model were the probability of discontinuing 3C Patch and the cost of ulcer treatment when using 3C Patch, standard care or where 3C Patch is discontinued and replaced with standard care. The EAC performed 2-way sensitivity analysis to explore the impact of varying the probability of discontinuing 3C Patch and the probability of healing with 3C Patch in weeks 6 to 20 simultaneously. The EAC recognised that there is likely to be interaction between these variables. The results suggested that if there is no discontinuation of treatment at 5 weeks (0% discontinuation rate), and weekly healing rates after week 5 are over 4.5%, then 3C Patch would be cost saving. However, this healing rate is significantly higher than the rate used in the EAC base case (2.7%), which was aligned with the Game et al. (2018) RCT and also used a 0% discontinuation rate.