We are happy that our recent editorial (1) stimulated interest from other experts in the diabetic foot. However, we find ourselves in disagreement with the letter by Jeffcoate and Game in this issue of Diabetes Care (2) in several respects. They suggest that our editorial betrays “a failure to understand how the structure of trials must be determined.” Surely, this cannot be the case. Any trial assessing dressings, drugs, or constructs should be designed to provide the maximum opportunity for the product to demonstrate efficacy by removing all possible confounding variables. As we have recently demonstrated (3), those patients provided with removable cast walkers only wear their device for 28% of activity daily, so we proposed that future trials should therefore standardize off-loading, preferably using a nonremovable device. As off-loading in the trial of promogram (4) was “left to the individual center,” we stand by our assessment that a likely explanation of the failure to demonstrate efficacy was related to a failure to standardize off-loading.

Having demonstrated the efficacy of any new product, it then behooves us to translate the results into clinical practice. Here we agree with Jeffcoate and Game that not all patients can tolerate casts; however, our experience to date suggests that the instant total contact cast (TCC) is better tolerated by patients than the TCC (5). (The instant TCC is a removable cast walker rendered nonremovable by wrapping it with cast material.) Further studies on this will be published in 2004. Rather than stating that many patients cannot tolerate nonremovable devices, surely research should be directed at improving the design of such casts to make them more safe and acceptable. We suggest that the failure to develop satisfactory off-loading in recent years is responsible for the poor results of trials of potential new therapies for plantar ulcers.

Jeffcoate and Game then assert that TCCs do not have dressing windows. Coincidentally, in the very next issue of Diabetes Care, Ha Van et al. (6) describe a TCC incorporating just such a window.

Further support for our position appears in several articles published in the months since the appearance of our editorial. In addition to describing the incorporation of a dressing window into a nonremovable cast, Ha Van et al. reported that only 10% of patients complied with the removable off-loading device in their studies, suggesting that the 28% reported in our study (3) was likely realistic, if not optimistic. Secondly, Caravaggi et al. (7) demonstrated that trials of new dressings could be successfully executed using a nonremovable cast. Finally, Piaggesi et al. (8) provide pivotal histological evidence strongly demonstrating the importance of adequate off-loading. It is now clear why so many trials have failed to demonstrate efficacy in recent years. Hence, we reiterate the need for a paradigm shift in the design of future clinical trials of putative therapies for plantar neuropathic ulcers.

1
Boulton AJM, Armstrong DG: Trials in neuropathic diabetic foot ulcers: time for a paradigm shift? (Editorial).
Diabetes Care
26
:
2689
–2690,
2003
2
Jeffcoate WJ, Game FL: Off-loading in trials in neuropathic diabetic foot ulceration: no, it’s not time for a paradigm shift (Letter).
Diabetes Care
27
:
635
–636,
2004
3
Armstrong DG, Lavery LA, Kimbriel HR, Nixon BP, Boulton AJ: Activity patterns of patients with diabetic foot ulceration: patients with active ulceration may not adhere to a standard pressure off-loading regimen.
Diabetes Care
26
:
2595
–2597,
2003
4
Veves A, Sheehan P, Pham HT: A randomized controlled trial of promogran vs standard treatment in the management of diabetic foot ulcers.
Arch Surg
137
:
822
–827,
2002
5
Armstrong DG, Short B, Espensen EH, Abu-Rumman PL, Nixon BP, Boulton AJ: Technique for fabrication of an “instant total-contact cast” for treatment of neuropathic diabetic foot ulcers.
J Am Podiatr Med Assoc
92
:
405
–408,
2002
6
Ha Van G, Siney H, Hartmann-Heurtier A, Jacqueminet S, Greau F, Grimaldi A: Nonremovable, windowed, fiberglass cast boot in the treatment of diabetic plantar ulcers: efficacy, safety, and compliance.
Diabetes Care
26
:
2848
–2852,
2003
7
Caravaggi C, DeGiglio R, Pritelli C, Sommaria M, Dalla Noce S, Faglia E, Mantero M, Clerici G, Fratino P, Morabito A: HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial.
Diabetes Care
26
:
2853
–2859,
2003
8
Piaggesi A, Viacava P, Rizzo L, Naccarato G, Baccetti F, Romanelli M, Zampa V, DelPrato S: Semiquantitative analysis of the histopathological features of the neuropathic foot ulcer: effect of pressure relief.
Diabetes Care
26
:
3123
–3128,
2003