The Balgrist University Hospital in Zurich is a tertiary referral center for DFI and amputations (emergency and elective consultations with a 24-hour service) and affiliated to the University of Zurich. Regarding DFIs, it resumes a multidisciplinary team composed of four diabetic foot surgeons, three internist physicians, a hospital pharmacist, five specialized wound nurses, two podiatry nurses, musculoskeletal expert radiologists, a diabetes nurse, three nutritionists, a shoemaker, a prosthesis specialist, and up to four infectious diseases physicians who are specialized in orthopedic infections. Moreover, this team is supported by an in-house company for orthopedic footwear (Balgrist Tec) and individual adaptations of off-loading devices, a re-education unit, physical therapy, a research campus (Balgrist Campus) with a BioBank, and an Unit for Clinical and Applied Research with nine study nurses and three personnel with experience in biostatistics and investigative designs (www.balgrist.ch). This research unit runs a register for DFI’s and DFOs. This register is presumably the largest in Switzerland. Our potential of recruitment oscillates between 1 to 4 new DFI episodes (hospitalized and outpatient patients) per week. This study will start at the Balgrist, but is expandable to other national or international centers.
Study: Two concomitant prospective-randomized trials
We will conduct two concomitant prospective-randomized clinical trials (RCTs) on the duration of postsurgical systemic antibiotic therapies for DFIs, including DFOs:
- First RCT (on residual infection after amputation): Its primary study question is if systemic antibiotic therapy can be shortened in amputated patients with eventual residual soft tissue infection or residual stump osteitis. The secondary study questions are the incidence of adverse events and overall costs related to the treatment.
- Second RCT (on the duration of systemic antibiotic therapy in non-resected infections): The primary study question is if antibiotic therapy can be shortened in non-amputated patients with soft tissue infections and osteitis. The secondary study questions are the incidence of adverse events and overall costs related to the treatment.
Definitions and eligibility criteria for participants
We will class DFI episodes according to the severity of infections and IDSA criteria (Infectious Diseases Society of America) . Mild infection is defined as having ≥2 manifestations of local inflammation (swelling or induration, erythema, tenderness, warmth, purulent discharge). Moderate DFI is erythema >2 cm, or involving structures deeper than the subcutaneous tissues . We define DFOs as a bone infection with any positive microbiological, histological and/or radiological evidence of bone involvement. We define remission as the absence of clinical, anamnestic, radiologic and/or laboratory signs of former infection. Of note, new or persistent necrosis, fracture, Charcot deformity or ulceration can be interpreted as remission as long they are no signs of infection. The anatomical area defining DFI for the study terminates at the ankle joints, but participants are eligible with leg infections as long as these originate in their diabetic foot. Table 1 resumes the inclusion and exclusion criteria.
Interventions and study conduct
For both RCTs, we keep the current therapeutic practices. Basically, amputation or disarticulation is foreseen for DFO with advanced bone destruction and terminal (painful) ischemia, but not for DFI per se. The amputation level will be kept as distal and as minimal. Basically, we will perform amputation on a level determined by MRI imaging and mechanical properties. All surgeries will be performed with the participation of an experienced surgeon. The patient will be invited to participate and will be allocated to a short or a long antibiotic treatment arm; further allocation depends of the surgical indications (amputation or conservative approach). The inclusion can occur until Day 4 of surgery or of effective antibiotic therapy.
Surgical indication: amputation: If the clinicians and the patient decide for amputation, the patients participate in the First RCT. If there is residual post-amputation infection remaining either in the soft tissue or bone, the patient will be randomized as follows:
- - 1 vs. 4 days for residual soft tissue infection
- - 1 vs. 3 weeks for an eventual residual proximal stump osteitis
Stop of all antibiotics if no bacterial growth at Day 4; or according to the randomization arm.
Surgical indication: debridement without amputation: If the clinicians and the patient decide for debridement only (no therapeutic amputation), then the patient is in the Second RCT:
- 10 versus 20 days for soft tissue infections
- 3 versus 6 weeks for non-amputated osteomyelitis
If the patient cannot participate in one RCT, he/she can participate in the other (Figure 1).
Table 2 reveals the variables of interest in each of the two RCT. The follow-up will be active (regular clinical consultations by the study investigators) until 2 months postoperatively, and passive (notification of recurrence, e.g. upon telephone contact) at 12 months postoperatively.
If the patient is operated, we will ask to sample intraoperative tissue for BioBanking for eventual further research, or completeness of the current studies. The BioBank will store intraoperative specimens, at ambient temperature (15–25°C) in the Balgrist Campus. The storage will be anonymous for 10 years, and financed by external grants.
MRI (Magnetic resonance imaging)
At Balgrist University Hospitals, each patient suspect for DFO has a conventional X-rays and MRI examinations as part of our standard clinical protocol. For this study, no patient will have scintigraphy in addition to the MRI. The standard MRI examination will be performed before surgery as part of the usual clinical approach. We will test no new software. Both RCT will not demand for additional radiologic exams only for study reasons.
Prior antibiotic therapy
A microbiologically effective antibiotic therapy beyond 96 hours prior to screening is an exclusion criterion. In contrast, we will allow a 72-hours window before debridement, independently of the duration of prior antibiotic administration. However, if the patient requires a new antibiotic agent based on microbiological results, independently of the duration of prior ineffective antibiotic therapy, there will be no minimal windows or maximal pre-debridement antibiotic durations and the patient can be included into both RCTs.
The antibiotic therapy is administered according to the IDSA guidelines . Initially, it is either empiric or targeted to the results of preoperative information. After 2-4 days, it becomes targeted to the susceptibility profile. The choice of the agent, and its administration route (oral or parenteral), is at the discretion of the treating clinicians. Nonetheless, for both RCTs, and to achieve a minimal homogeneity, we establish a list of “allowed antibiotics” (Table 3). We will avoid placebos, topical antibiotics and antiseptics; except for the eventual pre-incisional skin disinfection. Likewise, anesthesiologists will remain free to administer the routine perioperative prophylaxis (cefuroxime, vancomycin, or clindamycin for up to three doses), if they judge it indicated. Finally, we will collect the packages of the prescriptions during the outpatient treatment; as a surrogate of "proof" of the patient’s antibiotic intake.
Pregnancy and breast-feeding women
This study, all antibiotics and surgeries, have no specific relations to pregnant or breast-feeding women and their children. Additionally, the study population is likely not to reveal women at procreating age. Formally, we will not exclude pregnant and breast-feeding women, but the investigators will avoid antibiotics that are cautious for pregnant or breast-feeding women; according to the Swiss Compendium (www.compendium.ch).
Risks for the study participants
Besides the retrospective identification of patients in both RCTs, we ignore particular risks. For BioBanking specifically, a theoretical risk could be the detection of unknown pathologies. In such case, the investigators will engage to inform the patient orally or by letter; if he/she did not refuse it previously. Concerning both RCTs, a theoretical risk could be a higher incidence of recurrences in the corresponding short antibiotic arms.
Diabetic ulcer care and pressure relief
Standard diabetic ulcer foot care will include wound debridement (during hospitalization and visits and only if clinically indicated), daily care with dressing changes, pressure off-loading and professional diabetes control. Off-loading is defined as avoidance of all mechanical stress on the injured extremity. Because off-loading is so critical to the healing process, we will instruct patients to wear the device at all times except when bathing and to use a device at all times when walking or standing is required, eventually also during night rest. Strategies for off-loading will be standardized as follows: All ulcers on the bottom of the foot will be fitted with an off-loading device during the Baseline Visit 1. The size of the off-loading device (walker) will be determined based on the patient’s correct shoe size. We will insert the appropriate size of the insole inserted into the device. Once the target ulcer has been debrided, cleansed, dressed and secured, we will apply the device according to the manufacturer’s instructions for use.
Randomization and Allocation procedures
The unblinded allocation in a short or a long antibiotic duration arm, in both RCTs, will occur electronically 1:1 (randomization without blocked or matched variables). The result will be dichotomous. It will be either the “short arm”, or the “long arm” of antibiotic therapy. In a further step, the surgical indication (amputation vs. conservative therapy with debridement), as well as the infection site (soft tissue vs. osteitis) will finally determine the exact study arm and the corresponding antibiotic duration. We will use freely available randomization programs, e.g. (www.randomizer.org). The Principal Investigator, the Sponsor and two dedicated study nurses only will be allowed to randomize and to implement. They will conceal the randomization procedure electronically; and as printouts in the study documents.
The Unit for Clinical and Applied Research will assign an independent monitor (with experience in prospective-randomized clinical trials) to the study. All patient files, notes and copies of laboratory and medical test results must be available for monitoring. The monitor will verify all, or a part of the Case Report Forms (CRF), data and written Informed Consents. One monitoring visit at the investigator’s site prior to the start and twice during the study will be organized by the Sponsor. Furthermore, there will be a close-out visit at the study end.
Audits and Inspections
A quality assurance audit/inspection of this study may be conducted by the competent authorities. The quality assurance auditor/inspector will have access to all medical records, the investigator's study related files and correspondence, and the informed consent documentation. The investigator will allow the persons being responsible for the audit or the inspection to have access to the source data/ documents and to answer any questions arising.
Timetables and Study visits
For both RCT, we need 36 months each; starting in September 2019. Table 4 displays the overall study timeline. SPIRIT-Figure 2 resumes the timepoints on the study visits. Basically, all study patients will have weekly assessments, an end-of-treatment visit and a test-of-cure visit two months after. Another control will take place at 12 months, which only interests the question if there has been a recurrence during that year following the treatment. This last information can be gathered via a phone call, the patient's visit, or by the general practitioner of the patient, or the hospital's medical files. During the active study period, the assessments will be identical for both RCTs, the study objectives (primary and secondary outcomes), and their individual study arms (soft tissue vs. bone infection); with the only exception that patients in the shorter antibiotic arms will terminate the study earlier by one to three weeks. The aggregation of study-related information, laboratory data and clinical assessments on each study visit timepoints is summarized in Table 5.
Statistical analyses, study objectives and sample sizes
Statistical approach to the study objectives and Statistical Analysis Plan (SAP)
The primary objective for both RCT’s is the “remission of infection” at two months of postoperative follow-up times. The contrast to “remission” is “recurrence”. We will classify recurrence as “clinical recurrence” with recurrent or new infection in the former infection site, and as “microbiological recurrence” with the same pathogen(s) as for the index infection at the same infection localization. The secondary objectives are identical for both RCTs: the risk for adverse events in each randomization arm and the overall treatment costs.
Statistical techniques, study design and sample size calculations
Statistically speaking, both RCT's are simply to analyze and simple in the design. Therefore, we renounce on a formal and separate Statistical Analysis Plan (SAP). The Sponsor and the Principal Investigator wrote the analytic strategy together. Both RCTs are exactly the same non-inferiority studies; without adaptive study designs. Moreover, we apply the same non-inferiority design for the primary outcome "remission", as well as for the secondary outcome "adverse events". Regarding the outcome "treatment costs" we do not plan any non-inferiority requirements, since DFIs are multifaceted diseases with substantial interference with other expensive pathologies. The study objectives "clinical remission" and "adverse events" will be binomial variables; the objective "overall costs" will be expressed as continuous variables.
The expected clinical remission is set at 80% for each study arm; in both RCTs. Non-inferior margins are set at 20%: power 80%, alpha 5%. Excluding some anticipated drop-outs, we need for the First RCT (residual infection after amputation) 2 x 50 episodes regarding soft tissue infections; and 2 x 50 episodes for residual DFO. For the Second RCT (duration of antibiotic therapy in non-resected DFI), we equally require 2 x 50 episodes for soft tissue infections and 2 x 50 cases for DFO (Figure 2). Hence, the total overall study population will be 400 participants, while an individual patient can participate several times in either RCT; provided that each DFI episode occurs in another infection site.
For both RCTs, a Data Monitoring Committee will perform interim analysis after the inclusion of the first 40 episodes, and again at 100 episodes; and decides upon the continuation of the studies. If there are overt differences in terms of remission between the short and long antibiotic arms in all subsets of DFIs, we will terminate the study. During these interim analyses, we will equally check if the expected statistical power for the final analysis will not fall under our arbitrary limits of unacceptability. If this power becomes lower than 50%, we will consider the trial no more ethical. To balance a potential loss of power, we also may recruit 50 supplementary patients per RCT, if the trial has not been stopped.
Methods of data aggregation
The analyses will base on descriptive statistics (numbers, median values with ranges) and group comparisons (Pearson-χ2-test or the Fisher-exact-test for categorical variables; the Wilcoxon-ranksum-test for (non-parametric), continuous variables. Multivariate, unmatched, cluster-controlled (on patient’s level) Cox regression analyses will adjust for the large case-mix that we expect. If the study becomes multicentric, another cluster-level will be allocated to the individual hospitals. The Cox regression is the only survival analysis we will perform. We renounce on time series analyses, Log Rank tests or Kaplan-Meyer curves, because of the substantial case-mix and the limited determination of the clinical variable "antibiotic use" among all complex and mixed pathologies associated to diabetic foot problems.
Variables with a univariate association of p <0.2 will be included in the final model, while the duration of antibiotic therapy, the number of surgical debridements and the presence of angioplasties will be automatically incorporated into the final model. A minimal follow-up time of at least two months post-surgery is required to be included in the multivariable models. We will check for collinearity and interaction (effect modification) by interaction terms and Mantel-Haenzel estimates. The individual start in the Cox regression analysis will be the date of first debridement. The individual follow-up times will be censored at 12 months, death, or the date before the lost to follow-up. Since our RCTs will be prospective and the study population well balanced, we anticipate few missing data. Consequently, we plan no imputations and renounce on matched analyses. The requirement for the supposed non-inferiority will be computed using a χ2-analysis with the real differences displayed as percentage points and 90% confidence intervals in both outcome assessments (remission; adverse events); for each RCT and for each study population separately. The (two-tailed) statistical significance level will be set at p<0.05.
Presentation of the study populations
We will publish, regarding both RCTs the outcomes "remission" and "adverse events", the intent-to-treat (ITT) and the per-protocol (PP) database. We renounce on modified ITT (mITT) populations. The ITT participants, who have signed the Consent Letter, will consist of all randomized DFI episodes, even if patients drop off the study; or if there is protocol violation. The PP population will consist of all patients completing the study and who have not deviated significantly from the protocol. Importantly, the PP analysis will be restricted to the participants who fulfil the entire protocol requirements in terms of the eligibility, adherence to the intervention, and outcome assessment. It will represent the "best-case scenario" being studied. Both RCTs already incorporate two subgroups (soft tissue vs. bone infections). These makes a total of four subgroup analyses. There are no further subgroups planned (Figure 2). However, we keep the right to perform further (yet unidentified) subgroup analyses, if we would detect by chance any substantial particularities in the final results.
Ethical and regulatory aspects
The study is registered in the Swiss Federal Complementary Database („Portal“) and in the international registry ClinicalTrials.gov (Number NCT04081792). This study only will make use of antibiotics that are already authorized in Switzerland for DFO and corresponding soft tissue infections. The indication and the dosage will be used in accordance with the prescribing information and international guidelines . All drugs and doses in this study will be commonly used agents and related doses. The study protocol will not change without prior Sponsor and Ethical Committee’s approval. Amendments will be reported. Premature interruption will be reported within 30 days. The regular end of the study will be reported to the Ethical Committee within 90 days, the final study report shall be submitted within one year after study end. The Ethical Committee and authorities will receive annual safety reports and are informed about the study stop/end. The study will be carried out in accordance to the protocol and with principles enunciated in the current version of the Helsinki Declaration, Good Clinical Practice, and the Swiss regulatory requirements.
Patient Information and Informed Consent
We will inform potential participants about the study, its voluntary nature, procedures involved, expected duration, potential risks and benefits and any potential discomfort. All participants will be provided an Information Sheet and Informed Consent Form. The original Form stays in the study records. For the BioBank, the participants will sign a General Consent regarding personal clinical data and biologic material. The investigators will uphold the principle of the participant's right to privacy and that they shall comply with applicable privacy laws. Subject confidentiality will be further ensured by code numbers corresponding to the computer files. For data verification, the Ethics Committee and regulatory authorities may require access to relevant medical records, including the participants’ medical history.
Early termination of the study
The Sponsor may terminate the study prematurely in certain circumstances, e.g. ethical concerns, insufficient recruitment, when the safety of the participants is at risk, respectively, alterations in accepted clinical practice making the continuation unwise, early evidence of benefit or harm of the experimental intervention. All patients will be free to withdraw from participation in this study at any time, for any reason, and without prejudice. The reason for withdrawal should be documented wherever possible. The withdrawal will not affect the actual medical assistance or future treatments. On rare occasions, the investigators may terminate a patient’s participation to protect his/her best interest. After study termination, the evaluations required at the next scheduled clinical visits will remain.
During the entire study duration, all adverse events will be collected, fully investigated and documented in source documents and CRFs. The Sponsor will submit an annual safety report to the local Ethics Committee. For both RCT, a Data Monitoring Committee will perform interim analysis after the inclusion of the first 40 episodes, and again at 100 episodes; and decides upon the continuation of the studies. This Committee will consist of a urologist surgeon and an anaesthesiologist not involved in the study or in the future author lists.
Treatment by specialists
All surgeries will be performed in the participation of an experienced surgeon. The antibiotic therapy will be ordered by internists and infectious diseases physicians with therapeutic and academic experience in DFI treatments. The current medications of the study patients, as well as possible interactions, will be controlled during hospitalization by the Head of Pharmacy of Balgrist University Hospital and by the internists, on a weekly basis. The Infectious Diseases physicians and surgeons will assure this drug surveillance during the outpatient periods.
Definition and assessment of (serious) adverse events and other safety related events
An Adverse Event (AE) is any medical occurrence in a study participant, which does not necessarily have a causal relationship with the study procedure. A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of hospitalization, persistent or significant disability. Participants with ongoing SAEs at study termination will be followed until recovery or stabilization after termination. The investigators will make a causality assessment. All SAEs shall be reported within 24 hours to the Sponsor-Investigator. SAEs resulting in death will be reported to the Ethics Committee within 7 days. Patients will AE and leaving the study, will be treated off-study, without restriction, at the study sites.
Data handling and record keeping / archiving
We will save data using the secured software REDCap®. When the study is terminated, it will be saved in the same system. During the usual clinical treatment, all healthcare workers and administrators at Balgrist University Hospital will have access to the clinical data. After the end of therapy, however, the clinical and laboratory data can only be accessed by defined persons that have contributed to the project. These persons are two dedicated study nurses, the Principal Investigator, and the Sponsor. Radiological data will be stored in the institutions’ PACS systems according to the institutional standard at the Balgrist University Hospital.
Case Report Forms
We will generate an electronic Case Report Form in REDCap® for every participant and all data relevant to the study is going to be recorded by authorized persons. The participant ID numbers are automatically assigned in consecutive ascending form by the REDCap® system.
Analysis and archiving
For data analysis, we will export and analyze subject-related data from REDCap in a statistic software (IBM-SPSS and/or STATA). All health-related data will be archived in the REDCap for a minimum of 20 years. Before data export, we will remove all patient identifiers. Collection, disclosure, storage of data will be carried out in accordance with Swiss data protection regulations and the Human Research Act. The BioBank stores the intraoperative samples in accordance with laboratory guidelines as standard.