The Diabetic Foot Consortium Biomarker Platform Study: A New Approach to Advance Diabetic Foot Ulcer Healing

Abstract

Objective:

Platform studies are an innovative clinical trial design to evaluate multiple potential therapies simultaneously using a master protocol framework for more rapid discovery of critical new disease-modifying therapies. Initially pioneered in cancer clinical trials, platform studies have more recently been adopted for new vaccine trials and other disease states. This approach has not been used for biomarker(s) validation.

Approach:

We present the development and successful implementation of a master protocol for a platform study in the National Institute of Diabetes and Digestive and Kidney Diseases Diabetic Foot Consortium (DFC) that concomitantly tests multiple biomarkers that could be used to predict diabetic foot ulcer (DFU) healing outcomes in people with DFUs.

Results:

This flexible master protocol, allowing the study of multiple biomarkers in a perpetual manner, designed to be inclusive of a broad spectrum of people with DFUs operating under the mantra “No DFU Goes Unstudied” successfully collects participant data and biospecimens for biomarker development and validation in a standardized manner across multiple DFC sites.

Innovation:

Integrating multiple biomarkers with a rich database of participants’ clinical characteristics, patient-reported outcomes, and standard of care practices at various sites collected longitudinally over 52 weeks following a pragmatic approach and thus relevant to people with DFU as seen in today’s daily practice, enable their subsequent implementation at the point of care to guide timely personalized DFU management decisions.

Conclusion:

Leveraging this robust platform will help to identify new therapeutic targets and design and conduct effective interventional clinical trials for DFU wound healing, which could inform the standards of care.

Graphical Abstract

Cathie Spino, ScD

Keywords

biomarkers clinical network diabetic foot ulcers wound healing

INTRODUCTION

Diabetic foot ulcers (DFUs) have an estimated global burden of 19–34% of people with diabetes worldwide.¹ More than 1.6 million people are diagnosed with a DFU, and >100,000 amputations secondary to a nonhealing or infected DFU are performed each year in the United States.² People with DFUs face the burden of long-term treatments, a 20–30% risk of nonhealing and a 60% risk of infection.^1,3,4 The considerable advances in understanding the biology of diabetic wound healing have not translated to effective therapies with the last drug therapy approved by the U.S. Food and Drug Administration (FDA) in the late 1990s.⁵ The paucity of validated biomarkers for DFU healing that can be used in clinical trials for targeted entry criteria and monitoring therapy effectiveness has contributed to the difficulties of DFU therapy development. Another factor is clinical trial design that often has very narrow inclusion criteria, which make recruitment difficult and the results less relevant and generalizable for the broader DFU population.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded Diabetic Foot Consortium (DFC) was established to improve the clinical study of DFUs by building a clinical research network to validate and develop DFU biomarkers with the eventual goal of conducting clinical trials for innovative DFU therapies. The DFC consists of multiple academic clinical sites, a Data Coordinating Center (DCC), and biomarker analysis units.⁶ The DFC is committed to and has achieved recruitment of people with DFUs that reflects the diversity of Americans suffering from DFUs, as currently seen in daily practice, including those from rural and/or underserved locations.⁷ In addition, the DFC expanded its research scope to include studying the role of social drivers of diabetic foot disease (SDDFD), such as food insecurity, housing instability, limited health literacy, and poor social support, as well as by engaging with a broad spectrum of communities and wound care stakeholders.

The DFC initiated and completed two biomarker studies using the traditional approach of a single protocol for each biomarker. The c-myc study evaluated whether the nuclear localization of c-myc and phosphorylated glucocorticoid receptor could predict DFU healing.⁸ The transepithelial water loss (TEWL) study tested whether the measurement of TEWL could predict DFU wound recurrence.⁹ The DFC also initiated a biorepository protocol to collect biosamples from each of these protocols. From these experiences and the NIDDK funding announcement for studies to develop biomarkers using the DFC infrastructure, the DFC decided to pursue a platform approach⁶—the Predictive and Diagnostic Biomarkers for Diabetic Foot Ulcers: Open Wound Master Study (NCT06104969)—to capitalize on this clinical study design, to better leverage DFC resources, and to achieve the vision of “No DFU Goes Unstudied.”

Master protocols, initially pioneered in cancer clinical trials, are defined as “one overarching protocol designed to answer multiple questions”^10–15 with multiple substudies. They are well suited for biomarker studies where the data and biosamples collected in a common protocol can be distributed for multiple biomarker investigations of a single disease. Their use in a clinical research network, such as the DFC, allows for extensive substudies within the master protocol framework to optimally understand biomarker performance characteristics and to propose biomarker cutoff values to characterize good and poor clinical outcomes. Therefore, this innovative and rigorous approach represents a paradigm shift for DFU studies and provides a robust framework to support new and personalized clinical care practices and improve the care of all people with DFUs.

CLINICAL PROBLEMS ADDRESSED

The Open DFU Platform Study evaluates a highly relevant clinical problem, given the high prevalence and serious consequences of the DFU through several features that address challenges in DFU research. 1.

Use of broad entry criteria instead of narrow eligibility criteria. A recent report from the Wound Care Collaborative Community found that clinical trials exclude 92% of people with DFUs.¹⁶ Implementing restrictive entry criteria limits the generalizability of results while also slowing recruitment. Therefore, the broad inclusion criteria in the DFC master protocol—people with diabetes with an open foot ulcer as seen at the point of care—includes individuals with active infection and/or osteomyelitis. The few exclusion criteria are based on clinical evidence of an immediately planned intervention that would alter the natural DFU healing course, such as an ischemia grade of 3 in the wound, ischemia, and foot infection (WIfI) classification.¹⁷ The DFC master protocol enables an increased relevance of the findings to a majority of people with DFUs as seen in the contemporary daily practice.

Establishment of a large cohort size instead of multiple small studies. The master protocol has a large scope with a planned sample size of up to 5,000 participants across the United States, thus enabling a natural history cohort study based on current standard of care (SOC) methods across multiple, geographic, and socioeconomic diverse locations across the United States. The multiple sites and broad entry criteria allow robust recruitment, a problem often faced by DFU clinical trials. Although not as large as Qualified Clinical Data Registries or insurance claims databases, the data from each participant in the master protocol are collected and recorded in a standardized manner and not imputed en masse from the electronic health records.

Use of the WIfI instead of the Wagner Classification System. The DFC master protocol departs from decades of clinical studies in DFU, which rely on the nearly half-century-old classification system as proposed by Wagner.¹⁸ The WIfI classification was chosen because it includes separate grading of the wound, ischemia, and infection and has been externally validated for the prediction of both ulcer healing and lower extremity amputation within cohorts.¹⁹ Furthermore, according to the most recent guidelines from International Working Group on the Diabetic Foot, “in a person with diabetes and a foot ulcer who is being managed in a setting where appropriate expertise in vascular intervention is available, use WIfI scoring to aid decision making in the assessment of perfusion and likelihood of benefit from revascularization.”²⁰

Holistic characterization of participants instead of narrow focus. Healing of DFUs requires tremendous commitment by patients and their families to care for their wounds. Yet, individuals with DFUs often have comorbidities or other nonmedical limitations to receiving the optimal care for their DFUs. The master protocol collects information on comorbidities such as diabetes characteristics (type, duration, and microvascular complications), cardiovascular disease (coronary artery disease and cardiac revascularization), and history of hypertension, hyperlipidemia, myocardial infarction, heart failure, and angina and allows for the listing of other conditions as free text. To complement the collection of comorbid data, lab values include hemoglobin A1c, estimated glomerular filtration rate, and the urinary albumin creatinine ratio (mg/gm) and the dates they were collected. These factors could contribute to the description of DFUs as a mega-disparity because of the marked differences in amputation rates for DFUs based on race, socioeconomic status, and location.^7,21,22 The DFC master protocol includes questionnaires on the SDDFD with the Social Determinants Battery—Short Form and patient-reported outcomes (PROs) with (1) Michigan Neuropathy Screening Instrument,²³ (2) Diabetic Foot Ulcer Short Form,²⁴ (3) Patient-Reported Outcomes Measurement Information System (PROMIS) 4a Sleep Disturbance,²⁵ and (4) Short Form (SF)-12 Health Survey.²⁶ While some have been validated previously in individuals with DFU, these questionnaires were specifically selected to obtain a comprehensive portrayal of the individuals with a DFU across a broad spectrum of risk factors and comorbidities (e.g., medical, social) that have been shown to have a high impact on DFU risk, including healing. Therefore, the data that will be acquired during the master protocol will further current knowledge on the complex healing processes and may help identify new measures that should be included in the design of new clinical trials targeting DFU healing.

Targeting multiple instead of individual or restricted biomarker tests from each participant. The master protocol was carefully conceived to balance the collection of core biospecimens and data to address important clinical questions in the field, while having a flexible process to incorporate additional biospecimen and data needs as substudies. This core protocol with high interoperability enables testing of concomitant biomarkers from multiple biospecimens obtained in standardized fashion from each participant (wound debridement tissue, wound fluid, wound dressings, blood, and urine) and wound images and participant clinical data that allow individual and pooled hypotheses to be tested. The current core master protocol is sufficiently broad to incorporate ancillary biomarker studies, which were approved for funding after rigorous peer review. Several areas of focus of these studies synergistically evaluate interactions between bacteria and inflammation, along with combined proteomic and metabolomic results, and they are central to the master protocol. Key areas of focus include the various “-omic” approaches such as proteomics, oxidation–reduction reactions, microRNA, inflammation, and microbiome, some of which have the potential to concomitantly test shared biological pathways. Hence, these studies are important not only to predict healing but also to understand the biology underpinning the healing and nonhealing so that targeted therapies can be developed and tested.

Incorporation of the standards of care instead of protocolized therapies: Importantly, the study allows for the collection of master protocol research outcomes, while providers care for these individuals as they normally would as a part of standard care in their locale. The design uniquely enables the marriage of clinical care and research at the same time, reducing burden to a participant and pursuing high representativeness that is often lacking in DFU studies to date. Concurrently, the SOC elements, from the perspectives of both providers and individuals with DFUs, including off-loading prescriptions, vascular assessments, debridement, and other treatments and procedures, are recorded as part of the master protocol. In addition, the reasons for divergence from the SOC are also recorded to better understand the results and plan clinical trials.

Standardized core forms instead of available site-specific electronic health records collection. The patient-related data are collected on standardized case report forms (CRFs) that have been approved by all DFC steering committee members. Once the CRFs are approved, they are entered into our unified data entry and data management system (REDCap Cloud, nPhase, Inc., Encinitas, CA) that is built and managed by the DFC DCC at the University of Michigan (UM). Furthermore, to ensure the highest quality assurance, collection, and processing of biospecimens generated from enrolled participants, standardized protocols are described in the study manual of procedures. A central laboratory located at the UM provides kits to all clinical sites that standardize biospecimen collection and labeling and provides housing and long-term storage of participant biospecimens. Individual biomarker study investigators work with the DCC, so that biospecimens and linked participants’ clinical data are distributed for analyses in a timely fashion. Logistical workflows to dispense samples and a dashboard to track sample aliquots are managed by the DCC as well. These biospecimens, wound images, and participant data are a resource for the wound healing community and will eventually be stored in the NIDDK Central Repository (https://repository.niddk.nih.gov/home). Investigators interested in using these resources currently can submit proposals through the DFC website (https://diabeticfootconsortium.org/researchers/).

Extended study duration instead of short-term outcome assessments. The master protocol has been designed to shed light on the natural history of DFU healing, with up to 78-week follow-up using the well-defined, FDA-endorsed complete wound healing criteria.²⁷ Wound size is also collected so that comparisons of different definitions of wound healing based on clinical assessment and wound size over protocolized time periods (as defined above) can be analyzed to evaluate whether the current practice of assessing healing after 12 weeks is a valid duration.

Performing integrated statistical analysis instead of biomarker-specific analyses. A novel aspect of our study is the ability to perform integrated statistical analyses of multiple biomarkers, which allows estimation of their joint predictive capability as well as comparison of each biomarker’s individual predictive power. For instance, when biomarker overlapping rates are moderate to high, in the sense that there are sufficient participants with most of the biomarkers measured, recently developed data integration methods^28–30 based on constrained maximum likelihood or empirical likelihood methods will be applied to integrate the information about the biomarkers’ prediction capabilities from different substudies into the central data analyses. These methods work for both cross-sectional and longitudinal analyses, boosting statistical power while accounting for the study population heterogeneity in comorbidities, SDDFD, and other factors. When biomarker overlapping rates are low, in the sense that few participants have simultaneous measurements of most biomarkers, some of the unmeasured biomarkers are considered as missing and novel missing data techniques will be applied, including both multiple imputation and augmented inverse probability weighting methods, in the analyses,^31,32 see Supplementary Figure S1 for statistical method details.³³

10.

Expandability for additional studies instead of building individual study infrastructure. The master protocol provides high scalability through substudies that can be added or removed during the lifespan of the master protocol. The structure of the platform study has adopted two models to incorporate novel science into the master protocol. The first avenue is through the use of data and biospecimens already collected in the master protocol, and the second avenue is through the addition of distinct substudies. The former does not alter the master protocol, and the informed consent form (ICF) allows for the use of collected biospecimen and data. This contrasts with a substudy where new biospecimens or participant data are requested. Modifications to the master protocol and/or the ICF are required for the potential change to the visit structure or data collection. Both types of studies require approval from the Ancillary Studies Committee that rigorously reviews and assesses the scientific rationale and justification for each proposed project. More information on submitting proposals can be found on the DFC website.

Examples of recent additions to the master protocol are a substudy on pedal medial artery calcification scores as a predictor for wound healing that requires collection and reading of foot X-rays, as well as incorporating biophysical sensors to measure wound temperature, oxygen saturation, and wound impedance, and adding new CRFs to collect major adverse cardiovascular events (new clinical data) for a subset of participants.^34–42 This is just another example on how the flexibility of this platform study design can address multiple scientific questions simultaneously, incorporate pilot studies, and reduce the time, cost, and sample size required to reach definitive conclusions as compared with individual “umbrella-style” designed studies that are traditional for trials in this space (i.e., for trials of multiple drugs in one disease) and allows for adaptation to meet the demands of future scientific discovery.

MATERIALS AND METHODS

The DFC master protocol was designed with a high level of pragmatism and the ability to enroll the vast majority of DFUs participants, as seen in daily practice. It is thus poised to answer multiple scientific and clinical questions simultaneously and adapt to make the most efficient use of study funds and participants. By collecting a large set of biospecimens in a standardized fashion and characterizing many participants and DFU features, it has the potential to inform and facilitate future clinical trials.

Eligibility

Briefly, the master protocol is open to all individuals with an Open DFU with few exclusion criteria (Table 1). These eligibility criteria maximize the opportunity for patients with DFUs to participate in the study during their clinical visit. The rationale behind having broad inclusion criteria is to evaluate any type of DFU across the spectrum of care, including infection and osteomyelitis. The few exclusion criteria include the presence of gangrene, WIfI ischemia grade 3, planned revascularization, and ongoing participation in a DFU clinical trial because these may confound the protocol’s outcomes on DFU healing.⁴⁴

Table 1.

Inclusion and exclusion criteria

Inclusion Criteria
1. Provision of signed and dated informed consent form
2. Age 18 years or older
3. Clinically diagnosed with diabetes or meeting the American Diabetes Association criteria⁴³
4. Open foot ulcer, defined as an open wound from the malleolus down. This includes postsurgical wounds left open to heal by secondary intention. In case of multiple ulcers, the largest ulcer is considered the study index DFU
5. Agreement to adhere to protocol visits and provide all required biospecimens and clinical data
Exclusion Criteria
1. Participation in an interventional clinical trial for DFU within 1 month of Visit 1
2. Currently receiving radiation to target area or chemotherapy
3. Gangrene in any portion of the foot with the index ulcer
4. Planned revascularization or under evaluation for revascularization of the index limb for advanced ischemia within the next 4 weeks of week 0
5. Severe limb ischemia (SVS WIfI ischemia grade 3)
6. Any concomitant medical or psychiatric condition that, in the opinion of the investigator(s), would compromise the participant’s ability to safely complete the study
7. Previous enrollment in this study

DFU, diabetic foot ulcer; SVS, Society of Vascular Surgery; WIfI, wound, ischemia, and foot infection.

Data elements collected at study visits

At the baseline visit, a comprehensive set of data is collected on demographics, medical and wound history, quality of life, social factors, physical exam, and wound images. Wound debridement tissue, fluid and dressings, as well as blood are collected at baseline and at the week 4 visit; urine collection, although optional given potential participants’ burden, is also recommended for collection at baseline and at the week 4 visit. Participants are evaluated at week 2 and week 4 and monthly thereafter until week 52 or complete wound closure, which is defined as skin re-epithelization without drainage or dressing requirements at two consecutive visits 2 weeks apart.⁴⁵ In addition, as suggested by the Observational Safety Monitoring Board for the DFC, we included follow-up on index DFC wound recurrence in participants who healed at week 78. The protocol collects extensive participant data, including demographics, laboratory data, medications, comorbidities, SDDFD, and PROs, providing a comprehensive profile of DFU participants (see Fig. 1). PROs collected through the master protocol, including measures of neuropathy, sleep disturbance, and quality of life, can inform the design of future clinical trials by identifying patient-centered endpoints and guiding individualized intervention strategies. SDDFD data may be incorporated into predictive models by stratifying participants by socioeconomic, geographic, and social support factors, allowing for weighting of these variables to better understand disparities in DFU healing and to develop personalized care pathways.

Figure 1.

Organizational elements of the Diabetic Foot Consortium’s “Predictive and Diagnostic Biomarkers for Diabetic Foot Ulcers: Open Wound Master Study.” DFU, diabetic foot ulcer; Omics, branches of science; PRO, patient-reported outcome; SDDFD, social drivers of diabetic foot disease.

Endpoints

Several key endpoints are assessed that include (Table 2): proportion of participants with complete wound healing (as defined above) by week 52; proportion of participants who develop infections of the index DFU among those with no infections at baseline; proportion of participants who have an amputation of the limb associated with the index DFU; time to healing; and a broad battery of PROS including change in baseline to later of 52 week or confirmation visit in SF-12 Physical and Mental domain scores,²⁶ Diabetic Foot Ulcer Short Form subscores,²⁴ and PROMIS Sleep Disturbance scores,²⁵ see Figure 2 for the study schema and the Supplementary Tables S1 and S2 for protocol and endpoint details.

Figure 2.

Study schema for the platform study of open diabetic foot ulcers. ¹Most study visits are in-person clinic visits, except as otherwise indicated in the protocol. ²Biomarkers include blood, wound fluid, wound dressings, wound debridement (as clinically indicated), and urine (optional but encouraged). ³For participants whose DFUs have healed prior to week 52, a phone call or video visit should occur at week 52 and 78 to assess recurrence and wound status. For participants whose DFUs have healed at week 52, a phone call or video visit should occur at week 78 to assess recurrence. For participants whose DFUs have not healed by 52 weeks, a 6-month phone call or video visit should occur to assess healing and wound status. DFU, diabetic foot ulcer; F/U, follow-up; meds, medications; QOL, quality of life.

Table 2.

Core primary and secondary endpoints

Primary Endpoints
1. Proportion of participants with complete wound healing by week 52, defined as complete wound closure where there is skin re-epithelialization without drainage or dressing requirements at two consecutive study visits 2 weeks apart
2. Proportion of participants who develop infections of the index DFU among those with no infections at baseline
3. Proportion of participants who have an amputation of the limb associated with the index DFU
4. Measures of prediction performance (e.g., predictive power, AUC, ROC, Akaike information criterion) of biomarker(s) for each of the clinical outcomes
5. Proportion of eligible participants providing biospecimens by site and by type (serum, plasma, wound fluid, wound dressings, wound debridement tissue, and urine)
6. Proportion of biospecimens of adequate quality by type
7. Proportion of sites that prescribe the most current SOC into usual care, specifically for: (a) off-loading; (b) vascular assessment; (c) debridement; and (d) infection management per SOC
8. Proportion of participants who adhere to physician-prescribed SOC therapies for their DFU care
Secondary Endpoints
1. Time to healing, defined as the time (in weeks) from baseline to complete healing
2. Change from baseline to later of week 52 or confirmation visit in: a. SF-12 physical domain score b. SF-12 mental domain score c. DFS-SF subscale scores (leisure, physical health, dependence/daily life, negative emotions, worried about ulcers/feet, and bother by ulcer care) d. PROMIS Sleep Disturbance

AUC, area under the curve; DFU, diabetic foot ulcer; DFS, Diabetic Foot Ulcer Scale; PROMIS, Patient-Reported Outcomes Measurement Information System; ROC, receiver operating characteristic; SF, Short Form; SOC, standard of care.

RESULTS

Seven clinical sites have been activated in the Open DFU Platform Study: University of California San Francisco, UM, University of Pittsburgh, University of Arizona, Beth Israel Deaconess Medical Center, Northwell Health, and University of Southern California. Since the first participant was enrolled in June 2023, DFC enrollment has reached 557 DFU participants and yielded over 5,000 biospecimens as of July 2025 (Table 3). Sixteen percent of participants have completed the study per protocol, of which 7% completed the 6-month follow-up call (week 72). Participants have completed 3,135 visits for which clinical research coordinators have entered 25,110 CRFs, with more than 75% entered within 3 days and an overall median timeliness of data entry of 0 days (i.e., data were entered on the date of the visit). These clinical research data and biospecimens are currently used in one K23 grant, five R61/R33 grants, five ancillary studies, three supplements, six ancillary analyses, and one substudy. The work done to date across the biomarker validation projects included in the master protocol has resulted in 11 presented abstracts at national and international meetings and 7 manuscripts. Thus, in <2 years since the first participant enrollment, the DFC master protocol has provided the foundation for abstracts and manuscripts that deliver critical insights into biomarkers and healing in a diverse set of DFU individuals.

Table 3.

Baseline characteristics in the Diabetic Foot Ulcers Open DFU Platform Study. All eligible participants

Variable Statistic or Category	Overall ( N = 557)
Race
White	402 (71%)
Black or African American	92 (16%)
American Indian or Alaska Native	25 (4%)
Asian	6 (1%)
Multiracial	3 (<1%)
Unknown or not reported	34 (6%)
Ethnicity
Non-Hispanic or Latino/a/x	443 (79%)
Hispanic or Latino/a/x	107 (19%)
Unknown or not reported	12 (2%)
Sex
Male	437 (78%)
Female	125 (22%)
Age (years)
N	557
Mean	59.2
SD	11.6
Median	59.8
Min, max	27.3, 93.6
Diabetes disease duration (years)
N	555
Mean	17.3
SD	12.1
Median	15
Min, max^a	0, 80
Type of diabetes
1	44 (8%)
2	512 (92%)
BMI (kg/m²)
N	550
Mean	33.4
SD	8.5
Median	32
Min, max	17.9, 92.6
HbA1c (%)
N	479
Mean	8
SD	2.2
Median	7.5
Min, max	4.3, 15.7
Wound location
Plantar, n (%)	382 (69%)
Forefoot^b	169 (44%)
Midfoot^b	89 (23%)
Hindfoot^b	54 (14%)
Toes^b	70 (18%)
Ankle^b	0 (0%)
Nonplantar, n (%)	175 (31%)
Forefoot^c	65 (37%)
Midfoot^c	39 (22%)
Hindfoot^c	22 (13%)
Toes^c	37 (21%)
Ankle^c	12 (7%)
Previous therapy used on the study ulcer in the past 2 months, n (%)
No	166 (30%)
Yes	391 (70%)
Previous amputation, n (%)
No	243 (44%)
Yes	314 (56%)
WIfI wound
Intact skin with ischemic rest pain (requires typical symptoms + ischemia grade 3); no wound or gangrene	<1%
Small, partial loss of dermis presenting as shallow ulcer(s) on distal leg or foot; no gangrene or exposed bone, unless limited to distal phalanx	273 (49%)
Full-thickness ulcer with extension to ligament, tendon, joint capsule, or deep fascia without abscess or osteomyelitis, gangrenous change limited to digits	270 (48%)
Full-thickness deep ulcer with abscess, osteomyelitis, or joint sepsis with extensive Gangrene localized to portion of forefoot or midfoot or heel	12 (2%)
Missing	0 (0%)
WIfI ischemia
Ankle brachial index (ABI) ≥0.80; ankle systolic pressure >100 mm Hg; TcPO2 ≥60 mm Hg	505 (91%)
ABI = 0.6–0.79; ankle systolic pressure = 70–100 mm Hg; TcPO2 ≥40–59 mm Hg	32 (6%)
ABI ≥0.4–0.59; ankle systolic pressure >50–70 mm Hg; TcPO2 ≥30–39 mm Hg	7 (1%)
ABI ≤0.39; ankle systolic pressure <50 mm Hg; TcPO2 = 30 mm Hg	1 (<1%)
Missing	12 (2%)
WIfI foot infection type
Uninfected	475 (85%)
Mild	61 (11%)
Moderate	19 (3%)
Severe	2 (<1%)
Missing	0 (0%)

Site confirmed the observations being correct for the subject who reached the maximum value of diabetes disease duration.

b,c

Percents are calculated based on the number of plantar and nonplantar locations, respectively.

BMI, body mass index; DFC, Diabetic Foot Consortium; max, maximum; min, minimum; SD, standard deviation; TcPO2, transcutaneous oxygen pressure.

DISCUSSION

Two types of innovation are hallmarks of master protocols: the use of a trial network with infrastructure in place to streamline trial logistics, improve data quality, and facilitate data collection and sharing; and the use of a common protocol that incorporates novel statistical approaches to study design and data analysis, enabling a broader set of objectives to be met more effectively and timely than would be possible in independent trials.¹¹ The DFC master protocol includes both and represents a paradigm shift in the approach to clinical study of DFUs by being inclusive of all DFU patients—significant strengths of this design. Rather than studying a single question (e.g., does a product lead to improved healing time, or does this biomarker predict complete wound healing) or a specific patient population (e.g., Wagner grade 1 DFU), our biomarker platform study approach studies the whole spectrum of DFUs (see Supplementary Fig. S2). The infrastructure developed in the NIDDK DFC and now the Open DFU master protocol can be used to address multiple questions in parallel and be nimble to incorporate new questions as biomarkers and therapies advance. In taking a pragmatic approach to the SOC being followed in distinct and diverse geographic locations, our robust and standardized ICF, data collection, and safety reporting processes position us to address future efforts, such as embedding clinical trials within usual health care and creating learning health care systems. DFUs with their accompanying infections and amputations are common, costly, and deadly, and we hope that the adaptive biomarker platform study approach detailed here can be an exemplar for future investigations of other chronic disease states.

Case vignette

“A 62-year-old man with type 2 diabetes presents with a 2.5 cm plantar ulcer of 6 weeks’ duration on his right foot. Baseline assessment using a validated biomarker panel at the point of care featuring an elevated inflammation index and upregulated CCL28 chemokines identifies him as a high-risk non-healer. Using this information, the clinician applies more intensive personalized care earlier by initiating advanced wound therapies that include the use of cellular and tissue-based products immediately, continued aggressive off-loading with a DH off-loading shoe given the patient’s requirement to drive for work, and coordinating multidisciplinary follow-up, which included assessment with vascular and infectious diseases specialists. As a result, the ulcer demonstrates accelerated healing and closes by week 15, avoiding infection or further invasive interventions. This scenario illustrates how predictive biomarkers could enable timely, personalized interventions to promote wound healing and prevent complications.”

Limitations

Although the platform approach has many advantages, there are some limitations. Broad inclusion criteria and multiple substudies necessitate rigorous regulatory and ethical oversight, including comprehensive informed consent and monitoring for participant safety. Potential variability introduced by site-specific SOC practices is mitigated through standardized data collection, central training, and analytical methods that account for site and treatment heterogeneity. It requires sufficient funding to support the development and maintenance of the research infrastructure, and it is not well suited for individual center clinical trials. In addition, if proposed substudies are sufficiently different from the current platform design, it may be more efficient to start additional studies—whether traditional or alternative platform studies—rather than adapt the current platform study. For example, new endpoints such as ulcer-free days in remission⁴⁶ would likely require a change in the schedule of study visits to reflect the SOC differences from open to closed wound to recurrence and differences in collection methods (e.g., coordinator vs. patient) that would not fit easily into our current platform study design. New clinical outcomes that reframe the characterization of DFUs as healed or recurrent wounds within a framework of remission (as used in cancer care) could anchor biomarker discovery and validation to meaningful patient-centered outcomes, with the potential to ensure that advances translate into durable improvements in daily life and long-term health. The DFC encourages proposals to investigate such new scientific directions in collaboration with DFC investigators; more information about the proposal process is available at https://diabeticfootconsortium.org/researchers/.

In summary, the Predictive and Diagnostic Biomarkers for Diabetic Foot Ulcers Open Wound Master Study offers significant advantages for accelerating effective biomarker(s) validation and complex data integration for advanced modeling for wound healing, improving study efficiency, particularly in a complex and heterogeneous disease such as DFUs. The knowledge garnered from this study poises us to help design new interventional trials and personalized care approaches. The DFC team is actively monitoring and refining its implementation, including carefully considering logistical, regulatory, and statistical challenges to ensure validity, reproducibility, and success.

INNOVATION

With up to 5,000 U.S. participants followed for up to 78 weeks, the study is the largest to provide prospective data on DFU healing in real-world settings. The Open DFU Platform Study broader inclusion criteria (including individuals with infections or osteomyelitis) increase its relevance. The flexible protocol accommodates new substudies. Integration with SOC practices reduces participant burden. The use of the WIfI classification system^18,44 replaces outdated risk prediction models. Multiple prespecified biomarkers (Table 4), wound imaging, and clinical data are standardized and integrated using advanced statistical approaches, enhancing predictive capabilities, and enabling evaluations of novel biological healing pathways.

Table 4.

Prespecified biomarkers studied in the Diabetic Foot Ulcers Open DFU Platform Study

Biomarker	Biomaterial Use	Storage	Transport	NIH Reporter Grant No.
Inflammation index	Wound debridement tissue	4°C for 18–24 h, then −80°C	Frozen	R33DK131917
Microbial DNA	Wound debridement tissue	4°C for 18–24 h, then −80°C	Frozen	K23DK131261
Cysteine (Cys) and cystine (CysS)	Wound fluid	−80°C	Frozen	R33DK131909
Wound fluid microbiome—anaerobic activity	Wound swab	−80°C	Frozen	R33DK133846
Proteomic biomarkers	Blood (serum)	−80°C	Frozen	R33DK131915
Urinary microRNAs	Urine RNAs	−80°C	Frozen	R33DK131897

NIH, National Institutes of Health; RNA, ribonucleic acid.

KEY FINDINGS

Platform studies are an innovative clinical trial design to evaluate multiple potential therapies simultaneously.

The DFC has successfully applied the platform study approach to biomarkers of DFU healing by implementing and continuing to enroll participants in the first-ever master protocol for DFUs.

Over 500 participants have been enrolled, and thousands of unique data points, including links to biospecimens, are now available as a result of this national effort.

ACKNOWLEDGEMENTS AND FUNDING SOURCES

The authors would like to thank all the participants with DFU who have generously given their time to participate in DFC studies. The authors thank the NIDDK Project Officers, Henry Burch, MD and Yan Li, PhD, for study guidance, as well as all investigators, coordinators, and data coordinating staff listed in the Supplemental Acknowledgments.

This study was conducted by the NIH-sponsored DFC supported through Grant IDs U01DK119100, U01DK119083, U01DK119094, U01DK119099, and U24DK122927 of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

AUTHORS’ CONFIRMATIONS

B.S.: Writing—original draft, writing—review and editing, supervision, and funding acquisition. C.S.: Conceptualization, methodology, formal analysis, writing—review and editing, supervision, and funding acquisition. R.P.-B.: Conceptualization, methodology, writing—review and editing, supervision, and funding acquisition. C.S., B.S., and R.P.B. designed the MP. B.S. and R.P.B. drafted the article. B.S., C.S., R.P.B., M.K., G.G., and T.L.Z.J. participated in finalizing the MP. All authors have reviewed and approved the final version of the article.

AUTHOR DISCLOSURE AND GHOSTWRITING STATEMENT

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. The content of this article was expressly written by the authors, and no ghostwriters were used.

Footnotes

ABOUT THE AUTHORS

Brian Schmidt, DPM, Associate Professor, Department of Internal Medicine, UM. Cathie Spino, ScD, Research Professor, Biostatistics; Director, Statistical Analysis of Biomedical and Educational Research (SABER) unit; UM, DFC DCC PI. Teresa Jones, MD, NIDDK Project Scientist of DFC; Michael Conte, MD, Co-Director, UCSF Heart & Vascular Center; Chief, Division of Vascular & Endovascular Surgery. Gayle Gordillo, MD, Professor of Plastic Surgery, Pitt; Senior Medical Director of Wound Services & Pressure Injury Prevention & Outcomes, UPMC. Geoffrey Gurtner, MD, FACS, Professor & Chair, Department of Surgery; Professor of Biomedical Engineering, UArizona. Crystal Holmes, DPM, CWSP, Professor, Internal Medicine, UM; Director, Podiatry Services. Cathy Martin, MS, RN, BC-ADM, CDCES, Clinical Research Unit (CRU) Research Nurse, UM. Fleur Maturo, MS-CRM, CRU CRC, UArizona. Kourtney Noll, BHA, CRU CRC, UM. Steven Thelen-Perry, MS, SABER DCC Portfolio Manager. Nazila Mirzadjahromi, MSc, SABER DCC Project Manager. Chandan K. Sen, PhD, Bart Griffith Professor of Surgery, Pitt; Director, McGowan Institute for Regenerative Medicine; Associate Vice Chancellor for Life Sciences Innovation & Commercialization, Health Sciences; DFC Chair-elect. Rodica Pop-Busui, MD PhD, Professor & Endowed Chair, Division of Endocrinology, Diabetes, & Clinical Nutrition; Director, Harold Schnitzer Diabetes Health Center, Oregon Health & Science University; DFC Chair.

Supplemental Material

Abbreviations and Acronyms

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