The David Jenkins Portfolio Diet was originally designed to lower blood lipid levels in patients with hypercholesterolemia by emphasizing vegetables, fruits, grains, and legumes, while omitting animal products, and limiting saturated fat intake (46, 47). Specifically, the diet focuses on plant sterols (1 g/1000 kcals) as enriched margarine, soy and vegetable proteins (23 g/1000 kcals) as soy milk, meat alternatives, nuts, beans, chickpeas, and lentils, viscous fibers (9 g/1000 kcal) in the form of oats, barley, and psyllium, and low-calorie fruits and vegetables (46, 47) (Table 2). Following a comprehensive interventional trial in which 13 participants received the portfolio diet, a statistically significant reduction of LDL cholesterol, and coronary artery disease was observed (p < 0.001) alongside high compliance (93%) and acceptability (p = 0.042) (47). Similarly, in recent literature interventional trials have emerged assessing the efficacy of a WFPBD, like that of the portfolio diet, for neuropathic pain in individuals with diabetes. Specifically, in a trial assessing a low-fat plant-based diet, omitting animal products, and limiting fat intake to 20–30 g/day in 34 patients, a statistically significant reduction of pain on subjective neuropathy questionnaires and neuropathy on objective electrophysiology was observed (p < 0.05) (19). WFPBDs have been shown to provide sufficient glycemic control and lipid management which, when left unchecked, can exacerbate diabetes-related neuropathy. Given the absence of literature concerning the intersection of dietary lifestyle interventions and neuropathic pain of leprosy, it is hypothesized that a WFPBD will have similar physiological and neuro-protective benefits in a cohort of patients with leprosy and its neuropathic sequelae, in whom diabetes comorbidity is frequent.

Participants in the intervention group will be instructed to follow a WFPBD for 24 weeks. The study duration was chosen as a conservative estimate of comparable lifestyle-based interventional trials that demonstrated statistically significant improvements in diabetes-related neuropathy outcomes (18, 19). The diet will emphasize vegetables, fruits, whole-grains, nuts, and legumes, while omitting animal products, and limiting fat intake (Table 2). Selection of specific plant-based components may differ across study sites in concordance with local culinary preferences and cultural practices related to food. By tailoring the diet to the unique cultural diaspora affected by leprosy, many of which already endorse plant-based components, we seek to enhance adherence and acceptability to the diet overall. Likewise, current economic projections suggest that diets seeking to reduce animal products are more affordable than current standard diets across all socioeconomic levels – particularly due to inclusion of global staples such as tubers, beans, legumes, and rice – further enhancing accessibility (48–50). Participants will receive weekly support and guidance via 1 h counseling sessions with registered dieticians or the equivalent at each participating site. Sessions will be designed to disseminate comprehensive guidelines for following the WFPBD including culturally acceptable recipes and addressing concerns or knowledge gaps regarding the intervention. Participants in both the intervention group, and control group will be instructed to continue their respective leprosy therapeutics as prescribed throughout the duration of the study. Finally, dietary adherence will be measured via monthly random 24 h dietary recalls, and participants are free to withdraw at any point during the trial if they no longer wish to participate.

Clinical manifestations of leprosy are highly variable, hinging on several geographic, cultural, and genetic underpinnings (2). As such, to maximize the impact of trial outputs, we seek to address the global experience of leprosy through collaboration between the TDU in Toronto, Ontario, Canada, and one or more partner centres for excellence in the care of Hansen’s disease patients abroad. Given migration patterns, selected study centres will account for endemic source countries and regions including the Philippines, the Indian sub-Continent, Southeast Asia, and South America, providing for a more representative data set (2, 51). Trial documents including patient informed consent will be prepared in multiple languages to harmonize procedures across study sites. Likewise, site leads at each respective centre will be responsible for coordinating recruitment, as well as data collection. Oversight will be maintained by a centralized lead at the TDU, who will be responsible for disseminating the randomization protocol, and ensuring overall procedural adherence across sites.

Patients with a history of leprosy will be pre-screened for inclusion via clinical records prior to routine follow up. Study personnel will approach eligible patients experiencing active or treated (“cured”) leprosy, as well as subjective neuropathic pain at participating tropical disease institutions. Eligible participants will receive a comprehensive in-person review of the trial protocol, including data collection requirements, and will be given the patient consent form. Patients will voluntarily confirm willingness to participate and will be free to withdraw at any point. Upon consent to enrolment, participants will be randomized to either the WFPBD intervention group, or standard of care control group. To ensure equal distribution and matching between study groups, randomization will be carried out using a stratified block method (52). Participants will be assigned to strata primarily by study site, followed by sex (male/female), and lastly age-band (18–65, >65) (Figure 2). Random sequence generation will be carried out using a computer-generated allocation sequence. Study investigators, physicians, and participants will not be blinded to group allocation due to the transparent nature of the dietary intervention and counseling. However, primary end points will be collected by independent study personnel, blinded to group allocation, allowing for a single-blinded protocol.

This is a novel RCT addressing the implications of a WFPBD on neuropathic outcomes in individuals with leprosy. This relationship has not been directly assessed in the current body of literature, however similar research questions have been assessed in individuals with diabetes mellitus. As such, the sample size calculation herein will utilize this literature as a proxy. The efficacy of a WFPBD diet on neuropathy in a diabetes cohort has been reported via the Michigan Neuropathy Screening Instrument (MNSI), including both subjective (questionnaire) and objective (physical assessment) measures. The sample size calculation was based on the MNSI questionnaire measurement as explicit details pertaining to the MNSI physical assessment were not provided. Specifically, both the type of QST utilized (vibration, perception, both, etc.) and the location the test was carried out (lesion, glove, stocking, etc.) were not mentioned. Therefore, the MNSI questionnaire was preferentially chosen as a proxy. Participants receiving the intervention reported a final mean MNSI questionnaire of 5.3 ± 2.5 compared to 7.1 ± 2.8 in the control group at study end (19). Using an opensource sample size calculator with two independent study groups, continuous endpoints, an alpha of 0.5 and 80% power, a final sample size of approximately 60 participants was ascertained (53, 54). This is a conservative estimate as source literature demonstrated a statistically significant effect on outcomes with a relatively low population of 34 individuals (19). Assuming high acceptability and a 14% withdrawal and/or loss to follow-up rate based on previous literature, a final sample size of ~70 individuals, 35 per group, will be needed to adequately power this trial (19, 47, 55, 56).

Descriptive statistics including reported means ± standard deviation for continuous variables [questionnaires including MNSI-physical assessment, Neuropathy Total Symptom Score (NTSS), modified Medical Research Council Scale (mMRCS), Neuropathic Pain Symptom Inventory (NPSI), McGill Pain Questionnaire (MPQ), Pittsburgh Sleep Quality Index (PSQI), and International Physical Activity Questionnaire (IPAQ) summative scores, visual analog scale (VAS), anthropometrics, diabetes duration, hemoglobin A1c, and serum micronutrient levels] and proportions for categorical variables [number of adverse events, dietary adherence, insulin use, leprosy clinical status (according to the WHO and Ridley Jopling classification systems), frequency and prevalence of inflammatory leprosy reactions, corticosteroid use] will be reported by each study group (57). Between- and within-group comparisons will also be made for continuous variables using the Student’s t-test with reported p-values, and for categorical variables using the chi square or Fisher’s exact tests, reporting p-values with odds ratios and 95% confidence intervals. Statistics will also be reported for all time points including baseline, and end of study. Multivariate logistic regression adjusting for covariates [such as age, sex, PROGRESS+ factors (58, 59), level of physical activity, smoking status, alcohol consumption, comorbidities, diabetes status] and potential effect modifiers (such as change in weight over time, medication de-escalation over time) will be carried out to ascertain the impact of a WFPBD on PNP in leprosy patient sub-populations and under various conditions. All statistical analysis will be carried out using GraphPad Prism 8 (GraphPad, United States).

The MNSI is a robust assessment of neuropathy identifiers that includes both a subjective questionnaire and objective measurements of perception via QST. Specifically, Semmes-Weinstein monofilaments will be used to measure sensation at the ulnar nerve-innervated dorsum of the hand bilaterally, given this site’s predilection for leprosy associated nerve damage, while a 128 Hz tuning fork will be utilized to test for vibration perception thresholds at the great toe (43, 60). This screening instrument has been widely used and validated in both diabetes and leprosy related neuropathy cohorts (19, 60). Scoring is based on a binomial yes/no response to specific questions where yes = 1 point and no = 0 points. Additionally, any abnormal QST result = 1 point, and a score of 4 or greater indicates the presence of neuropathy (60). The MNSI will be conducted at both baseline and at study end and will be utilized as one of the measurements for sensory neuropathy (Figure 3).

The Neuropathy Total Symptom Score will also be used to formulate a more robust assessment of sensory neuropathy. Unlike the MNSI, the NTSS includes considerations for both neuropathy intensity and frequency. Based on a summative questionnaire, participants can be assigned a maximum of 21.96 points, indicating greater morbidity, and depicted as a matrix comparing neuropathy intensity (mild, moderate, severe) versus frequency (occasional, often, continuous) (61). This questionnaire has been widely used and validated in cohorts of individuals with diabetes, a common comorbidity of leprosy, and will strengthen the assessment of sensory neuropathy within this trial (23, 61). The NTSS will be carried out at both baseline and study end (Figure 3).

The modified Medical Research Council Scale is a reliable tool that has been commonly used to measure motor neuropathy in patients with leprosy (43). The mMRCS utilizes voluntary muscle testing (VMT) in the assessment of motor nerve function including the facial, ulnar, median, radial, and later popliteal nerves. Patients can be assigned a maximum of 5 points, which may be downgraded by any significant reduction of VMT. A score of less than 5 is indicative of decreased motor nerve function (43). The mMRCS will be utilized at baseline and at the end of study to provide a robust assessment of motor neuropathy in this trial (Figure 3).

The Neuropathic Pain Symptom Inventory incorporates both measures of pain intensity and frequency including common patient pain descriptors such as burning, squeezing, pressure, and stabbing relative to the past 24 h (62). It has most commonly been used in the assessment of neuropathic pain in leprosy cohorts, wherein the higher the score the greater the pain, out of a possible 100 points (62–64). Participants will complete the NPSI questionnaire as part of a comprehensive neuropathic pain assessment at both baseline and at the end of the study (Figure 3).

The McGill Pain Questionnaire will also be used to assess neuropathic pain throughout the trial, given a more robust set of patient pain descriptors. The MPQ classifies over 75 words into 4 descriptive pain categories including sensory, affective, evaluative, and miscellaneous, each with subcategories utilizing a scaled point system to indicate relative severity within each group, as well as over time. A maximum score of 78 points is possible, indicating most chronic and severe pain (65). This questionnaire has been utilized and validated within both diabetes and leprosy cohorts (19, 66). Alongside the NPSI, the MPQ will also be completed at both baseline and at the end of the study to provide the most comprehensive assessment of neuropathic pain possible (Figure 3).

Participants will also subjectively assess pain level on a 10-cm Visual Analog Scale between absolute poles of “No pain” and “Worse possible pain,” both at baseline and at the end of the study. The VAS is a tool commonly used to assess pain given any underlying etiology, including both diabetes and leprosy, and is often utilized as the gold-standard when validating novel questionnaires assessing pain (19, 62, 63).

Additional considerations concerning the longstanding implementation of a WFPBD within this population will also be assessed at each counseling session. Data on safety via the number of adverse events, tolerability via drop-out rate, and emerging harms, against gold standard PNP therapeutics (or non-interventions, such as watchful waiting) will be collected and summarized. Dietary adherence reported as a proportionate yes/no will also be collected to ensure interventional feasibility. Based on the current landscape of the literature a WFPBD is expected to perform as well, if not better, than the current standard of care when considering implementation (19, 47, 55) (Figure 3).

As a dietary lifestyle intervention can have a drastic effect on anthropometrics, height and weight will be measured at both baseline and at the end of the study and will be used to calculate body mass index (BMI) (Figure 3). Likewise, sleep quality has been associated with neuropathy severity, and must be monitored throughout the trial. The Pittsburgh Sleep Quality index is a validated questionnaire, widely used to assess sleep perturbation due to various etiologies. Participants can be assigned a maximum of 21 points indicating severe difficulties in all areas of sleep quality (67). The PSQI will be collected at baseline and at the end of the study. Self-reported physical activity will also be collected at such intervals using the International Physical Activity Questionnaire. The IPAQ includes 27-items designed to gauge the frequency and intensity of physical activity carried out in a 7-day period, encompassing occupational, transportation, housework, and leisure activities. It has been extensively tested and validated throughout 12 countries and has previously been utilized in assessing self-reported physical activity in both diabetes and leprosy cohorts (68–70). To avoid the potentially confounding effects of additional lifestyle levers, such as sleep quality and exercise, these assessments are paramount during downstream analysis. Lastly, in individuals experiencing a biochemical diabetes due to leprosy related corticosteroids, an assessment of diabetes control including duration of illness, therapeutics used, and insulin status will also be carried out to monitor any changes throughout the trial (Figure 3). Standard biochemistry, including serum cholesterol, triglycerides, hemoglobin-A1c, serum glucose, hepatic transaminases, creatinine, and basic micronutrient panel (e.g., serum ferritin, B12) will be taken to measure diabetes parameters and general physiological status. To better ascertain the relationship between the dietary lifestyle intervention and leprosy itself, neuropathy and neuropathic pain outcomes will be stratified by secondary outputs, with specific emphasis on diabetes status, and steroid use.

In order to avoid additional invasive blood draws in at-risk equity-deserving patient populations, alternative yet validated measures of individuals’ micronutrient status will be implemented. Both skin carotenoids and urine metabolites can be utilized to define the baseline dietary habits of all participants. Resonance Raman Spectroscopy (RRS) has emerged as an inexpensive and non-invasive tool commonly used to measure skin carotenoid levels including alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin (71, 72). Due to the high concentrations of carotenoids in fruits and vegetables, RRS has been used to reliably estimate dietary intake of such foods (71, 72). Its performance has been assessed across multiple geographies and in patients with varied skin tones, and a statistically significant correlation was not identified (71, 72). Similarly, urine metabolites can be assessed using standard laboratory biochemistry commonly available to study centres and can be utilized to estimate the remaining components of diet (73, 74). Consumption habits of fruits, vegetables, low fiber grains, fish protein, nuts, red meat, shellfish, dietary supplements, caffeine, alcohol, and fats and oils can be estimated and corroborated using relative levels of urine metabolites including methyl glutamate, mannitol, cytosine, suberate, omega 3, tryptophan, xylitol, lysine, creatine, vitamin B2, and vitamin E (73, 74). Micronutrient status assessment will be carried out at baseline and at study end to ensure significant micronutrient derangements have not occurred (Figure 3).