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Interventional Clinical Trials on Diabetic Peripheral Neuropathy: A Retrospective Analysis

Aims/Introduction Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. At present, there is no comprehensive summary of the clinical trials related to DPN. In this article, we summarized the basic characteristics of the interventional clinical trials pertaining to DPN to determine the current status of research in this field and the existing issues. Materials and Methods We searched the World Health Organization International Clinical Trial Registration Platform (ICTRP), PubMed and Web of Science for clinical trials from 2005 to April 2021 and extracted 149 registered and 459 published clinical trials on DPN. We summarized the characteristics of the clinical trials, including the source registration, recruitment status, stage, age group, allocation method, intervention, end point classification, funding source, and treatment. Results After excluding noninterventional and nontreatment trials, 149 registered clinical trials out of 292 records from 12 registration centers and 459 published articles were included in this study. Among the registered trials, 43% had been completed, and 34.4% had been published in peer-reviewed journals. Among these trials, more than half used random allocation and blinded placebo-controlled methodologies. A total of 40.3% of the trials were multicenter studies, 63.8% of the treatments were drug therapies, and the endpoint classifications of 49% were efficacy and safety. Of the 459 published interventional clinical trials on DPN, 69.7% of the trials used drug treatments; more than half were randomized, double-blind, placebo-controlled clinical trials; 94.1% had positive outcomes; 46.4% had a target size of 50; and 22.9% were multicenter. Conclusion This paper systematically summarizes the current status of interventional trials on DPN registered in the ICTRP and published clinical trials and provides a reference for the development of high-quality intervention strategies for DPN in the future.


Introduction
According to the International Diabetes Federation (IDF), the global prevalence of diabetes will rise to 578 million by 2030 and 700 million by 2045. 1 Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes, 2 and 50% of diabetic patients eventually develop neuropathy during the course of their illness. 3 DPN is defined as symptoms of peripheral nerve dysfunction after other reasons are excluded. 4 Patients with DPN usually have numbness, tingling, pain or weakness that starts at the distal ends of the limbs, with the characteristic stocking-glove distribution, and progresses to the proximal ends. 5 Many DPN patients suffer from chronic and severe neuropathic pain, which is difficult to treat and manage, seriously influencing their quality of life, imposing a heavy burden on them and increasing their medical costs. 6 Currently, the treatment for DPN relies on prevention, blood sugar control, and pain and symptom control. 7 Many patients do not receive effective treatment methods, and drug therapy is still the main treatment for DPN. 8,9 The lack of efficacy and the occurrence of side effects of the drugs currently used for the prevention and treatment of DPN are serious clinical problems, and there is an urgent need to conduct in-depth research to develop new strategies. 10 Clinical trials are pivotal in evaluating the efficacy of novel interventional therapies for different diseases. 11 It is necessary to summarize the current status of clinical trials on DPN to improve awareness among researchers and doctors and promote current and future therapies and interventions. The World Health Organization (WHO) International Clinical Trials Registration Platform (ICTRP: http://www.who.int/ictrp) is a global database that aims to make information regarding all clinical trials involving human beings publicly available. 12 At present, there is no summary of the clinical studies on DPN registered in the ICTRP. We systematically summarized the characteristics of ongoing and completed interventional clinical trials on DPN with the aim of determining their current status and future research directions.

Data Source and Search Strategy
The preparation for this study occurred in three steps: (1) we obtained the registration records of clinical trials on DPN as of December 2020 in the WHO ICTRP Search Portal (http://apps.who.int/trialsearch) using the term "diabetic peripheral neuropathy"; (2) two investigators (MW and ZZ) used standardized strategies to manually search for peer-reviewed publications of completed clinical trials that involved searching for the publication in the ICTRP database, followed by searching in PubMed and Google Scholar using the NCT number or the short title of the trial and the name of the main researcher if the publication was not confirmed; and (3) the investigators reviewed the published clinical trials according to the preferred items for reporting systematic reviews and meta-analyses (PRISMA) guidelines. 13 The databases were searched from the database inception to December 2020, and the language of publication was limited to English in PubMed and the Web of Science.

Data Extraction and Selection
All registered clinical trials were included regardless of language. The retrieved records from the ICTRP were exported to Microsoft Excel for filtering by title, abstract, and availability of the full-text article from March 31, 2005, to April 20, 2021 to exclude clinical trials on topics other than DPN. Then, we conducted an advanced search using the terms "diabetic peripheral neuropathy" and

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"intervention" to obtain interventional or treatment trials on DPN for further analysis. Interventional clinical trials on DPN were identified and confirmed. Noninterventional or nontreatment trials were excluded after screening the full-text articles. The following data were extracted from the clinical trial records in the ICTRP database and entered into Excel: source register, recruitment status, trial phase, eligibility criteria (age group and sex), allocation, intervention model, number of arms, endpoint classification, placebo comparator, participating center, masking style, target size, treatment, condition, primary outcome, and secondary outcome. The type of funding for the clinical trials, such as whether the trials were funded by industry, was determined by the identification of the primary funding source. Before the data were extracted, the original registration website was visited to ensure that the data were current. The primary and secondary outcomes were classified and analyzed according to the items listed on the original website, and those that could not be classified were listed as "other". The publication was confirmed by matching the research characteristics outlined in the ICTRP database with the corresponding descriptions in the published manuscript. If multiple publications pertained to the same registered trial, the first article to report the main results was selected, and the others were excluded. We performed a systematic literature review and searched for published clinical trials on DPN from the date of the inception of the database to April 2021, excluding unlisted and unrelated studies. The first author (MW) used a predefined form to extract the following data, which were then entered into Microsoft Excel: title, year of publication, intervention duration (weeks), sample size, treatment, masking/blinding, randomized controlled trial design, placebo comparator, participating center and outcome.

Discrepancies
The data analysis was conducted by two researchers (MW, ZZ), and any differences between the two researchers were resolved. If the two researchers could not reach an agreement, the final decision was made by a third researcher (XL).

Statistical Analyses
Missing values were excluded from the analysis unless otherwise indicated. Descriptive statistics were used to describe the characteristics of the clinical trials. Categorical variables are expressed as frequencies and percentages. SAS software was used for all statistical analyses (version 9.3, SAS Institute Inc., Cary, NC, USA). GraphPad Prism 8.2.1 (GraphPad Software, San Diego, CA, USA) was used to construct the histograms and pie charts.

Basic Characteristics of Interventional Clinical Trials on DPN
A total of 292 registered records of interventional clinical trials on DPN were retrieved from the ICTRP. Among these trials, 54 noninterventional trials were excluded: 50   observational trials, three factorial trials, and one diagnostic test trial. After screening the full texts of the remaining studies, 89 nontreatment trials were excluded, including 13 trials on supportive care, 67 trials with unknown/missing information, and nine other trials. Finally, 149 records of interventional clinical trials on DPN were included for further analysis ( Figure 1). As shown in Figure 2, we found that these 149 trials were registered from 2005 to 2021, with approximately ten registrations every year. In 2020, the number of interventional clinical trials on DPN was two times that in the previous year. We found that Clinicaltrials.gov had the largest number and earliest submissions of interventional clinical trials on DPN, and all other registration platforms had fewer than 10 trials ( Figure 2, Table 1). With regard to recruitment, we found that 49.7% of the trials had completed recruitment. Approximately 68% of the clinical trials had a target size of fewer than 200, 31.5% of which had a sample size of less than 50. More than half of the trials were single-center studies, and approximately 87.2% of the trials focused on adults/ elderly people. Most trials were randomized (77.9%) and blinded (63.7%), but approximately 51.7% of the trials did not use a placebo as a control. Trials in Phase II accounted for 30.9% of the total. Approximately 71.8% of the intervention models were parallel assignments. Drugs (63.8%) were the most common interventional treatment, followed by devices (16.8%). The endpoint classification in 49% of the trials was "efficacy and safety", followed by efficacy alone in 34.9%; however, 78.5% of the trials had no available results. The most common funding source was industry (53.7%), and nearly 51% of the trials were conducted in North America.

Interventional Characteristics of 149 Clinical Trials on DPN
Based on our analysis, there were nine types of interventions for the treatment of patients with DPN: drugs; devices; exercise; medical foods; genetic/biological therapies; revascularization; hyperbaric oxygen therapy; lifestyle modification programs; and massage/acupuncture. Of the 149 trials, three-fifths focused on drug interventions, followed by 19.4% focusing on supplementary alternative therapies and 16.8% focusing on devices, as shown in Figure 3A. In the 95 trials on drug therapies, 34.2% involved the symptomatic treatment of DPN; 17.5% involved pathogenetic treatments of DPN, and 12.2% were on other pharmacologic agents. These drugs included antidepressants, anticonvulsants, topical medications, opioid analgesics, nonopioid painkillers, vitamins and their derivatives, ion channel drugs, and traditional Chinese medicine ( Figure 3B).
Anticonvulsant drugs, such as pregabalin, gabapentin, carbamazepine, and pregabalin, are most commonly used for the treatment of DPN. Moreover, some new drugs have emerged, such as the new nonopioid analgesic drugs SKL11197, SR419, and LX9211. In addition, clinical trials were performed to investigate the effects of certain drugs on the nourishment of nerves, such as vitamins and their derivatives, caper extracts, and green tea extracts. As shown in Figures 3C, 25 device intervention trials included management/therapy systems (3), wearable aids (3), laser treatments (4), electrical stimulation (13), peristaltic pulse pneumatic compression devices (1), and extracorporeal shock wave therapy (1). Among the 25 trials on devices, electrical stimulation as an auxiliary treatment measure accounted for half. An overview of these interventions in the 149 clinical trials on DPN is shown in Table 2 and Figure 3.
Primary and secondary outcomes were used to directly reflect the objectives of the clinical trials and assess the

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efficacy of the intervention or drug treatment. 14 We summarized the primary and secondary outcomes of the 149 interventional clinical trials and found 313 primary outcomes and 725 secondary outcomes. The evolution of DPN pain was the most common evaluation index, accounting for 31.9% of the primary outcomes and 22.3% of the secondary outcomes. Among the primary outcomes, clinical symptoms or signs accounted for 16.9%, and neurophysiology accounted for 13.1%. The categories and percentages of the primary outcomes and secondary outcomes in the 149 interventional trials are listed in Table 3.     (147), pharmacokinetics (5), noninterventional treatments (46), reviews (83), animal or in vitro studies (30), and other topics (62). Finally, 459 articles were included in the analysis (Figures 2 and 4). Similar to the results of the analysis of registered clinical trials, the main interventions in the published articles were drugs, and more than half of the clinical trial designs were randomized, double-blind, and placebo controlled. The intervention time period was evenly distributed, but only 4.6% of the studies had an intervention duration lasting 12-16 weeks. In total, 46.4% of the studies had target sizes smaller than 50, and 77.1% of the articles reported single-center studies. Of the drug-related interventional trials, 28.5% focused on symptomatic treatment of DPN, and 18.1% focused on pathogenetic treatments. Among the device-related interventional trials, 58.5% investigated electrical stimulation. Peripheral nerve pain was used as the evaluation criterion (Tables 5  and 6, Figures 5 and 6).

Discussion
Through the ICTRP search portal, we identified recent clinical trials on DPN and completed the first summary and extensive investigation of the 149 registered clinical trials on DPN from 12 registries. Half of the clinical trials involving adult/senior patients did not use placebo, were conducted in a single center and were supported by industry funding. Most of the trials had small sample sizes (<200), used parallel interventions and investigated different drugs. However, only approximately 22% of trials have available results, and 30% of those trials have published the results in a peer-reviewed publication.
Comprehensively analyzing the status of clinical trials on DPN is difficult if the ICTRP platform is not updated in a timely manner. Therefore, we searched In this study, the target size of most registered and published clinical trials on DPN was less than 50, which may be related to the large proportion of Phase I to Phase II study trials among the registered trials. In studies involving vulnerable and underrepresented populations, early studies, and trials on rare diseases, a small sample size is reasonable. 15,16 However, in most trials, a sample size that is too small will lead to inaccurate estimates in descriptive studies and inaccurate representations of statistical significance in analytical or comparative studies. 17,18 Some drugs and treatments require a large sample size for investigation and verification. [19][20][21] Therefore, it is necessary to include a large sample size to estimate the reliability and validity. In addition, single-center studies were common, and half of the clinical trials were concentrated in North America. Although the homogeneity of the samples is thereby ensured, these trials cannot meet the diversity and capacity requirements, cannot meet the regulatory requirements in multiple regions and do not reflect the clinical experience in different locations. 22 Therefore, multicenter research can avoid the limitations of single research, and the conclusions can have wider generalizability and greater credibility. 23 Our study found that 30% of clinical trials on DPN have been published in peer-reviewed journals, and more than half of these trials were randomized, blinded, placebo-controlled, and multicenter studies. Moreover, all published clinical trials reported positive results, which provides a scientific basis for the development of future clinical trials on DPN. However, 70% of the trials are still unpublished. The reasons they remain unpublished may be time constraints, resource limitations, rejection by journals, or bias against publishing negative results. These are important reasons for the low publication rate. Failure to publish is improper scientific behavior, as unpublished evidence is not available as a reference for the scientific community and clinicians. 24 Therefore, the results of completed trials should be actively published, ensuring that they can serve as a reference for future clinical trials and thereby avoiding wasting resources by unnecessarily repeating research.
Neuropathic pain affects approximately one-third of patients with diabetes, 25,26 and DPN is a key factor in the development of diabetic foot ulcers, the most common cause of amputation. 14 With the discovery of risk factors for DPN and a deepening understanding of the pathogenesis, 27 many researchers have developed effective treatments for DPN. Clinical trials have focused on various treatment strategies for specific pathogeneses of DPN. However, the treatment methods in these studies are only available in a few countries/regions. 27,28 Our research found that 17% of DPN clinical trials and 18% of published DPN clinical trials were for pathogenetic treatments. However, there is currently no treatment that  can prevent or reverse DPN; instead, treatment is limited to pain management. 27,28 In addition, our results revealed that 34% of DPN clinical trials and 29% of published DPN clinical trials were for symptomatic treatment. In our study, drugs were the most commonly used intervention, followed by devices, and then drug studies focused on anticonvulsants, aldose reductase inhibitors, and antidepressants. However, drugs for neuropathic pain are associated with many side effects, such as nausea, dizziness, dry mouth, and weight gain, which occur in 40% of the population and are dosedependent. 29 Due to changes in the pathogenesis of DPN, the efficacy of ARIs may be limited. 30 Although many ARIs have been successfully developed in in vivo and in vitro experiments, they have failed in most clinical trials due to adverse drug reactions and inadequate efficacy. 31 The safety and effectiveness of medical products need to be reviewed before they are used in the general population, which is supervised and implemented by the Food and Drug Administration (FDA). Drugs can be approved by the FDA in a variety of ways. 32 FDA approval of a new drug is associated with an increase in the publication of clinical trial registrations and reports of results for the drug. 33 However, the failure of new DPN drugs approved by the FDA may be related to the low annual registration rate of clinical trials, the delay in reporting test results, the low publication rate of articles or the stage of the clinical trial. Therefore, in future research, we should develop drugs based on the pathogenesis of DPN and reduce side effects. External treatments of DPN include topical drug therapies and device treatments. For patients who cannot tolerate oral medications, topical medication is a good choice. The most common local analgesics are lidocaine, capsaicin, and amitriptyline. 29 Lidocaine patches can improve the quality of life of patients with DPN, and their efficacy is equivalent to that of pregabalin. 34 Capsaicin can reduce pain and improve sleep quality in patients with DPN. 35 Our study found that 11 clinical trials investigated topical drugs as interventions, and 7% of the published clinical trials involved topical drug therapies. Topical drug therapies are safe and effective and are a valuable choice for the treatment of DPN. Due to oral drug intolerance and the high proportion of elderly patients, the development of topical drugs has great potential. 10,36 Research on device treatments has shown that highfrequency spinal cord stimulation is a safe and effective means of providing analgesia, and pulsed electromagnetic fields can regulate neuropathic pain and nerve impulses. 37 Plantar electrical stimulation can improve the ankle brachial index and enhance motor ability and plantar sensation in patients with DPN. 21 In this study, we found that electrical stimulation device studies accounted for half of the studies on devices. Electrical stimulation has no contraindications or side effects and may be an effective alternative and adjuvant therapy for DPN. 38

Conclusions and Future Perspectives
This report is the first summary of the registration of DPN clinical trials in the ICTRP Registration Platform and the However, this summary for DPN clinical trials had several limitations. First, we cannot guarantee the absolute reliability of the results. We only provide an overview of the characteristics of the clinical trials on DPN. We did not have access to the complete trial plans and data, and we were unable to evaluate the shortcomings and advantages of the trials. Second, we only retrieved publications from 22 trials. There may be more clinical trials to be published, but we did not contact the main investigators to verify the situation. Third, we only identified published clinical trials on DPN in the PubMed and Web of Science databases, and we may therefore have missed some published clinical trials.
In the future, we hope that more multicenter, largesample, placebo-controlled, randomized DPN clinical trials would provide high-quality clinical evidence. In addition to pain scores, comprehensive outcome indicators such as quality of life, quality of sleep, and psychological status should be considered as secondary outcomes. Collectively, this study could provide a reference and new insights for future DPN interventional trials.