Abstract: We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor β2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials. Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I2 = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I2 = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I2= 74%, five trials). In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I2 = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence) Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I2 = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.

Plain-language summary: The review authors searched the medical literature up to 3 March 2015, and identified 28 relevant medical trials, with a total of 2365 participants. The trials were performed in ten different countries, generally in out-patient settings. All the trials had low numbers of participants, which makes potential overestimation of benefits and underestimation of harms more likely. Half of the trials were sponsored by the pharmaceutical industry that produces these growth factors. The trials tested 11 different types of growth factor, usually by applying them to the ulcer surface. Growth factors had no effect on the risk of having one toe or more amputated when compared with either another growth factor, or placebo (inactive fake medicine), or standard care alone (evidence from four trials). However, when compared with placebo or no growth factor, growth factors seemed to make complete healing of ulcers (wound closure) more likely to occur (evidence from 12 trials). None of the trials reported data on participants’ quality of life. Harms caused by treatments were poorly reported, so the safety profile of growth factors remains unclear. It is clear that more trials are required to assess the benefits and harms of growth factors in the treatment of diabetic foot ulcers. These trials should be well-designed, conducted by independent researchers (not industry-sponsored), and have large numbers of participants. They should report outcomes that are of interest to patients, such as: how many of the participants’ ulcers healed, and how long the healing took; any level of amputation in the foot; quality of life; ulcer-free days following treatment; and harms caused by treatment, including whether there are any potential cancer risks.