Submitted:
13 December 2024
Posted:
20 December 2024
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Abstract
Introduction an objective: Urinary tract infections (UTIs) are a significant health concern with high costs and poor quality of life (QoL) impact. Managing recurrent UTIs (rUTI) in women requires effective treatments that relieve symptoms and reduce recurrence, while also sparing antibiotics due to rising resistance. This study evaluates the efficacy of a nutritional supplement in reducing UTI recurrences and improving QoL compared to antibiotic therapy. Materials and Methods: This is a multicentric case-control study involving female patients with rUTI. We compared the efficacy of a dietary supplement containing D-mannose 3gr, Palmitoylethanolamide 600 mg, N-acetylcysteine 600 mg, Lactobacillus rhamnosus 2x109, Hibiscus extract 400 mg- (1 sachet/day for 14 days per month for 6 months) against a low dose of Fosfomycin 3 g (one sachet every 10 days for 6 months). Patients were clinically (age, BMI, hormonal status, smoking, and sexual activity) and microbiologically (urine cultures with antibiograms) evaluated at baseline, after 3 months, and after 6 months of therapy. Validated questionnaires were administered to evaluate QoL (WHO-5) and satisfaction (PGI-I). UTI was defined by positive urine culture (bacterial load ≥105 CFU/ml) and patient reported lower urinary tract symptoms (LUTS). Results: A total of 55 patients were enrolled in the nutritional supplement group (NGroup) and 34 in the Fosfomycin group (FGroup). In the NGroup, the median age was 62.2±16.0, a median BMI of 27.2±3.8, 13 (23.6%) were smokers, 29 (52.7%) were sexually active, and 42 (76.4%) were postmenopausal. The mean number of UTI at baseline was 1.87±0.75, decreasing to 0.51±0.63 at 3 months (p<0.001) and 0.28±0.54 at 6 months (p<0.001). Adverse events (AEs) reported were 2 (3.6%) at 3 months and 1 (2.1%) at 6 months (mild gastrointestinal symptoms in all cases). Questionnaires indicated improvements in both QoL (WHO-5: 18.90±3.91 at 3 months and 20.2 ± 2.55 at 6 months; p<0.001) and satisfaction (PGI-I: 3.04±1.61 at 3 months and 2.43±1.26 at 6 months; p<0.001). In the FGroup, demographic data revealed a median age of 62.9±12.9, a median BMI of 23.5±3.0, 10 (29.4%) were smokers, 30 (88.2%) were postmenopausal and 18 (54.5%) were sexually active. The mean number of UTI at baseline was 2.68±0.81, also in this group we have an improvement at 3 months 0.87±0.54 (p<0.001), and at 6 months 0.67±0.80 (p<0.001). No AEs were reported. QoL improved (WHO-5: 17.80±1.40 to 21.4±2.19, p<0.001), but satisfaction declined (PGI-I increased from 2.20±0.41 to 4.05±0.69; p<0.001). No statistically significant differences were observed between the 2 groups in terms of demographic data (except for BMI), AEs, WHO-5 questionnaire scores, and UTI changes (p>0.05). Lower satisfaction was observed in FGroup. Conclusions: Despite the limitations of this study, including a small patient population and the absence of a third placebo control group of patients, the oral preparation containing D-mannose, PEA, N-acetylcysteine, Lactobacillus rhamnosus and hibiscus extract may be a viable alternative to antibiotics for reducing rUTI in women.
Keywords:
recurrent female UTI
; adverse event
; nutritional supplement
; fosfomycin
Introduction
Urinary tract infections (UTIs) are one of the most common outpatient infections, and are more common in females, with 30–50% of females experiencing a UTI in their lifetime, as compared with men at 20%. [1,2,3] Acute UTI is most often uncomplicated cystitis and occurs in 50-80% of women in the general population. [6] Recurrent UTIs (rUTIs) are defined as two or more episodes of uncomplicated UTI in the preceding six months, or three or more episodes diagnosed over one year. [1,2,3,4,5] rUTIs can impact a patient’s quality of life (QoL), as persistent symptoms can be debilitating and is a risk factor for antimicrobial resistance and severe infections. [2,3,5] One-quarter of women who experience UTI go on to experience rUTI. [1] Precisely because they are so frequent, the management of uncomplicated rUTI in women is of great interest.
Physiopathologically UTI are commonly caused by ascending infection into the bladder via the urethra by rectal bacterial flora that reside in the periurethral area that replicate in the bladder to cause cystitis and urinary symptoms. [7] rUTIs are often caused by various factors such as the impaired host immunity or presence of structural or functional abnormalities of the urinary tract. [7,8,9] The primary causative agent of UTIs is the bacterium Escherichia coli, which normally resides in the intestinal tract but can migrate to the urinary tract and cause infection, but other bacteria, such as Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus saprophyticus, can also contribute to UTIs. In some cases, UTIs can be caused by fungal or viral pathogens, although they are less common. [10,11]
Active UTIs should be treated empirically, with passage to more directed antibiotic treatment once urine culture results become available. [7] Prevention of future episodes with antibiotic prophylaxis is supported by all guidelines and needs to be offered to those patients suffering from rUTIs. [12] According to 2024 EAU guidelines, continuous antimicrobial prophylaxis is recommended to prevent UTIs. Regimens include nitrofurantoin 50 mg or 100 mg once daily, fosfomycin trometamol 3 g every ten days, trimethoprim 100 mg once daily. [5] However, the overuse and misuse of antibiotics have led to the emergence of antibiotic-resistant bacteria, making the treatment of UTIs more challenging. As a result, there is growing interest in alternative approaches, including natural compounds and preventive strategies, to support urinary tract health and reduce the incidence of UTIs. [13]
In this study, we aim to evaluate the efficacy of an oral preparation containing D-mannose, PEA, N-acetylcysteine, Lactobacillus rhamnosus and hibiscus extract in the non-antibiotic prevention of rUTI, comparing it with conventional low-dose antibiotic prophylaxis. The objective is to develop an effective, well-tolerated therapeutic strategy with minimal or no side effects compared to antibiotic use to enhance the QoL for patients.
Materials and Methods
Patient and Dataset
This is a multicenter case-control study conducted in the Urology department of Florence and in the Gynecological department of Pisa, which prospectively enrolled female patients with UTIs from January 2023 to January 2024. The study aims to evaluate the efficacy of the non-antibiotic therapy with the nutritional supplement (composed of D-mannose 3gr, Palmitoylethanolamide 600 mg, N-acetylcysteine 600 mg, Lactobacillus rhamnosus 2x109, Hibiscus extract 400 mg) in preventing rUTIs, comparing it with a group of patients treated with Fosfomycin Trometamol 3gr. The study includes female patients presenting with lower urinary tract symptoms (LUTS) caused by a urinary infection, diagnosed with a midstream urine culture and treated with antibiotics according to sensitivity testing to resolve the infection at baseline prior to enrollment. In the nutritional supplement group (NGroup), patients were treated a food supplement product, as a non-antibiotic preventive therapy, following a regimen of one sachet per day for 14 days per month for six consecutive months. The group consists of female patients treated with low-dose antibiotic therapy using Fosfomycin Trometamol 3 gr (FGroup), one sachet every 10 days, as recommended by guidelines, for the same six-month period. Clinical and microbiological data were collected at baseline, after three months, and after six months. Follow-up visits included clinical examinations, microbiological analyses with midstream urine cultures, and completion of QoL and satisfaction questionnaires. The evaluated clinical and demographic data included age, BMI, sexual activity, smoking status, and hormonal status. The administered questionnaires included the WHO-5 (Well-being Index) to assess QoL and the Patient Global Impression of Improvement (PGI-I) to evaluate patient satisfaction. During the follow-up period, urinary infections with a microbial load ≥105 CFU/ml of a single uropathogen were assessed in urine cultures, along with associated LUTS, evaluating the number of UTIs, the number of antibiotic cycles, and any adverse events (AEs) from the antibiotic or the nutraceutical.
Statistical Analysis
Statistical analysis was performed using GraphPad Prism 10 (GraphPad Software). Data are presented as mean ± standard deviation (SD) or, number observed with percentages (%). To analyze the outcomes after treatment, two-tailed matched-pairs Wilcoxon test was performed. To analyze the range of scores, Chi-square test for trend was performed. The values of p<0.05 were considered significant.
To compare the FGroup and the NGroup, an unpaired two-tailed Mann-Whitney test was performed. To analyze outcomes after treatment Kruskal-Wallis test followed by Dunn's multiple comparisons test. The values of p<0.05 were considered significant.
Results
In the study, 55 patients were enrolled in the NGroup and 34 patients were in the FGroup receiving low-dose antibiotic therapy. The demographic characteristics and data regarding the comparison before and after therapy with nutritional supplement are presented in Table 1. The median age was 62.2±16.0, the median BMI was 27.2±3.8, 13 patients (23.6%) were smokers, 29 (52.7%) were sexually active, and 42 (76.4%) were postmenopausal. At baseline, the mean number of infections was 1.87±0.75, specifically: 17 (30.9%) of the patients reported one UTI, 30 (54.5%) reported two, 6 (10.9%) reported three UTIs, and 2 (3.6%) patients reported four UTIs. For these urinary infections at baseline, the median number of antibiotic courses was 1.35±0.98, with 16 (29.1%) patients having undergone one course of antibiotics and 1 (1.8%) patient requiring four courses. After 3 months of treatment with nutritional supplement, the mean number of UTIs was 0.51±0.63, with 31 (56.4%) of the patients experiencing no infections, 20 (36.4%) developing a single UTI, and 4 (7.3%) developing two infections. At 3 months, there was also a reduction in antibiotic use, with a median of 0.49±0.66, where 33 (60%) did not require any antibiotics and only 5 (9.1%) of the patients needed two courses. At the 6-month follow-up, there was a further reduction in the number of UTIs, with a median of 0.28±0.54, and 36 (76.6%) of the patients did not develop any infections, while only 2 (4.3%) developed two infections. At 6 months, 37 (78.7%) of the patients did not require any antibiotic therapy. An analysis comparing the number of infections and the need for antibiotic therapy at baseline and after treatment with nutritional supplement revealed a statistically significant reduction both at 3 months (<0.001) and at 6 months (<0.001). At 3 months, 2 (3.6%) AEs were recorded, while 1 (2.1%) was noted at 6 months. In analyzing the QoL and patient satisfaction questionnaires, these indicated improvements in both QoL (WHO-5: 18.90±3.91 at 3 months and 20.2±2.55 at 6 months; p<0.001) and satisfaction (PGI-I: 3.04±1.61 at 3 months and 2.43±1.26 at 6 months; p<0.001).
The demographic characteristics and data related to the baseline comparison and subsequent controls for the FGroup are described in Table 2. In the FGroup, the median age was 62.9±12.9, the median BMI was 23.5±3.0, 10 (29.4%) of the patients were smokers, 18 (54.5%) were sexually active, and 30 (88.2%) were postmenopausal. At baseline, there was a mean of 2.68±0.81 UTIs reported, with a median number of antibiotic courses also at 2.50±0.66. After 3 months of low-dose prophylactic antibiotic therapy, the mean number of UTIs was 0.87±0.54, with 5 (20.8%) of the patients not developing any infections, and the median number of antibiotic courses was 0.87±0.54. At the 6-month follow-up, there was also a reduction in the number of UTIs to 0.67±0.80, with a median number of antibiotic courses of 0.47±0.73. The comparison of data demonstrated a statistically significant reduction in the number of UTIs and the need for antibiotics at both 3 months (<0.001) and even more so at 6 months (<0.001). No adverse effects were reported in this group of patients.
Evaluating the questionnaires revealed a statistically significant improvement (<0.001) in QoL as measured by the WHO-5 score, with scores rising from 17.80±1.40 at 3 months to 21.4±2.19 at 6 months of therapy. Meanwhile, concerning satisfaction measured by the PGI-I, a subjective deterioration was noted regarding long-term continuous antibiotic therapy, which was statistically significant (<0.001), with scores changing from 2.20±0.41 at 3 months to 4.05±0.69 at 6 months.
Table 3 presents the results comparing the NGroup to the FGroup. Among the demographic variables, only the BMI showed a statistically significant difference between the two groups (NGroup 27.2±3.8 vs. FGroup 23.5±3.0), while the other variables were comparable. The number of antibiotic courses at baseline was significantly greater (<0.001) in the FGroup compared to the NGroup. For the remaining variables analyzed, no further differences were observed; thus, both therapy with nutritional supplement and low-dose antibiotic therapy were effective in reducing the number of infections at both 3 and 6 months of continuous treatment, maintaining an good QoL and greater satisfaction with nutraceutical product.
Discussion
The results of the present study demonstrate the effectiveness of the D-Mannose, Palmitoylethanolamide (PEA), N-acetylcysteine (NAC), Lactobacillus rhamnosus (LR04), and hibiscus extract (HiBCYN) in the treatment of rUTI. The association of these substances allowed a check of the growth of pathogenic and opportunistic microorganisms, in particular species of known resistance such as E. coli, helping to prevent urinary tract infections recurrence.
In this study, most patients with UTIs were postmenopausal women. The literature has reported that uterine muscles weaken, and vaginal Lactobacilli decreases in menopausal women due to reduced estrogen. Moreover, it has been reported that UTI pathogens, particularly Enterobacteriaceae, are responsible for colonization because of the increased pH levels. [14]. Considering these facts, postmenopausal women have a higher risk of developing UTIs.
The combination of D-Mannose, Palmitoylethanolamide (PEA), N-acetylcysteine (NAC), Lactobacillus rhamnosus (LR04), and hibiscus extract (HiBCYN) has shown excellent compliance in almost all cases of the women subjected to the study. The effectiveness
is demonstrated by the clear reduction of local symptoms (dysuria, stranguria and frequency) and in the significant reduction in the number of episodes of cystitis in women treated with the dietary supplement.
Interest in D- Mannose for treating UTIs dates back to the 1970s, when the initial cases of antibiotic-resistant uropathogens led to the exploration of alternative approaches to antibiotic treatment whenever possible. [15; 16] Some studies have shown that D-mannose can stop Escherichia coli from sticking to the urothelial cells by binding to the bacteria’s FimH fimbriae, which helps them attach to the bladder's epithelial cells. [17;18] Because of this action and the fact that it doesn’t have significant side effects, D-mannose is a safe and effective way to help prevent recurring UTIs. [19;20] In this study we used 3000 mg per day of D-mannose.
Palimitoylethanolamide (PEA) is a molecule similar to an endocannabinoid that plays a significant role in managing UTIs due to its anti-inflammatory and analgesic properties. Its primary action involves activating the PPAR-alpha receptor, which helps reduce inflammation and pain. [21] Additionally, PEA can form a protective layer in the urinary tract, preventing the adhesion of uropathogens while supporting the barrier function of the urothelium. Furthermore, PEA is considered safe with minimal adverse effects, making it suitable for long-term use. [22,23,24,25]
In our study N-acetylcysteine (NAC) was used because it offers a protective effect on the urothelium. [26] and furthermore Lactobacillus rhamnosus contributes to the urinary microbiota by producing lactic acid, which lowers urinary pH and creates an unfavorable environment for pathogenic bacteria. Additionally, it can establish a protective barrier by producing antimicrobial substances. [27;28] Additionally t has significant diuretic effects that improve kidney function. It also possesses anti-inflammatory properties by inhibiting the production of cytokines and enzymes, thereby reducing inflammation. It is considered safe, but excessive use may lead to gastrointestinal disturbances. [29;30]
Thus, both the mechanism and site of action of each component were considered to be unique, with the hypothesis being that, in combination, they would provide enhanced preventative efficacy than either ingredient alone.
In the group treated with antibiotic we have chosen low dose prophylaxis with Fosfomycin because it is a first-line treatment in Italy and several other countries.
When a comparison was made between the UTI episodes before and after the treatment, similar results were compared with the group using Fosfomycin. After 3 months of treatment with nutraceutical, the mean number of UTIs was 0.51±0.63, with 31 (56.4%) of the patients experiencing no infections, 20 (36.4%) developing a single UTI, and 4 (7.3%) developing two infections. At 6 months, 37 (78.7%) of the patients did not require any antibiotic therapy. An analysis comparing the number of infections and the need for antibiotic therapy at baseline and after treatment with nutritional supplement revealed a statistically significant reduction both at 3 months (<0.001) and at 6 months (<0.001). This finding suggests that UTIs can be treated without using antibiotics.
In addition, evaluating the questionnaires revealed a statistically significant improvement (<0.001) in QoL in both groups, as measured by the WHO-5 score, with scores rising from 17.80±1.40 at 3 months to 21.4±2.19 at 6 months of therapy with dietary supplement. Meanwhile, concerning satisfaction measured by the PGI-I, a subjective deterioration was noted regarding long-term continuous antibiotic therapy, which was statistically significant (<0.001), with scores changing from 2.20±0.41 at 3 months to 4.05 ± 0.69 at 6 months.
Overall, treatment with oral preparation containing D-mannose, PEA, N-acetylcysteine, Lactobacillus rhamnosus and hibiscus extract per 6 months was safe and well-tolerated. The treatment of rUTI with dietary supplement has the potential to provide a cost-effective strategy for managing women suffering with rUTIs, as was shown in a decision-analysis model comparing the effectiveness, cost, and health-related quality- of-life outcomes associated with commonly used strategies for the management of recurrent UTIs [31].
Conclusions
Overall, our study suggests that the nutritional supplement utilized is protective for rUTI (versus Fosfomycin) with possibly similar effectiveness as antibiotics. Furthermore, this study determined that this oral preparation positively impacts the patient’s well-being and it also appears well tolerated with minimal adverse side effects.
Despite the limitations of this study, including a small patient population and the absence of a third placebo control group, the nutritional supplement utilized may be a viable alternative to antibiotics for reducing rUTI in women.
The potential for resource savings and reductions in antibiotic usage are important objectives and, if confirmed, will be a significant step forward.
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Table 1.
Demographic Data and Comparison of parameters Before and After treatment with nutraceutical product n=55.
Table 1.
Demographic Data and Comparison of parameters Before and After treatment with nutraceutical product n=55.
| Age, years | 62.2 ± 16.0 | |||
| BMI | 27.2 ± 3.8 | |||
| Smoke status | ||||
| no | 42 (76.4%) | |||
| yes | 13 (23.6%) | |||
| Sexual activity | ||||
| no | 26 (47.3%) | |||
| yes | 29 (52.7%) | |||
| Hormonal status | ||||
| premenopausal | 13 (23.6%) | |||
| postmenopausal | 42 (76.4%) | |||
| Baseline (a) n= 55 | 3-months (b) n= 55 | 6-months (c) n= 47 | p-value | |
| n° UTI | 1.87 ± 0.75 | 0.51 ± 0.63 | 0.28 ± 0.54 | <0.001 a vs b-c |
| 0 | 0 (0.0%) | 31 (56.4%) | 36 (76.6%) | <0.001 a vs b-c; b vs c |
| 1 | 17 (30.9%) | 20 (36.4%) | 9 (19.1%) | |
| 2 | 30 (54.5%) | 4 (7.3%) | 2 (4.3%) | |
| 3 | 6 (10.9%) | 0 (0.0%) | 0 (0.0%) | |
| 4 | 2 (3.6%) | 0 (0.0%) | 0 (0.0%) | |
| n° cycles ATB | 1.35 ± 0.98 | 0.49 ± 0.66 | 0.25 ± 0.53 | <0.001 a vs b-c |
| 0 | 13 (23.6%) | 33 (60.0%) | 37 (78.7%) | <0.001 a vs b-c; b vs c |
| 1 | 16 (29.1%) | 17 (30.9%) | 8 (17.0%) | |
| 2 | 21 (38.2%) | 5 (9.1%) | 2 (4.3%) | |
| 3 | 4 (7.3%) | 0 (0.0%) | 0 (0.0%) | |
| 4 | 1 (1.8%) | 0 (0.0%) | 0 (0.0%) | |
| WHO-5 (score 0-25) | 18.90 ± 3.91 | 20.2 ± 2.55 | 0.059, ns | |
| PGI-I (score 1-7) | 3.04 ± 1.61 | 2.43 ± 1.26 | 0.081, ns | |
| 1 | 8 (14.5%) | 12 (25.5%) | 0.037 | |
| 2 | 17 (30.9%) | 16 (34.0%) | ||
| 3 | 12 (21.8%) | 11 (23.4%) | ||
| 4 | 9 (16.4%) | 4 (8.5%) | ||
| 5 | 4 (7.3%) | 3 (6.4%) | ||
| 6 | 2 (3.6%) | 1 (2.1%) | ||
| 7 | 3 (5.4%) | 0 (0.0%) | ||
| Adverse Events | 2 (3.6%) | 1 (2.1%) |
Table 2.
Demographic Data and Comparison of parameters in Fosfomycin group n=34.
| Age, years | 62.9 ± 12.9 | |||
| BMI | 23.5 ± 3.0 | |||
| Smoke status | ||||
| no | 24 (70.6%) | |||
| yes | 10 (29.4%) | |||
| Sexual activity | ||||
| no | 15 (45.5%) | |||
| yes | 18 (54.5%) | |||
| Hormonal status | ||||
| premenopausal | 4 (11.8%) | |||
| postmenopausal | 30 (88.2%) | |||
| Baseline (a) n= 34 | 3-months (b) n= 24 | 6-months (c) n= 30 | p-value | |
| n° UTI | 2.68 ± 0.81 | 0.87 ± 0.54 | 0.67 ± 0.80 | <0.001 a vs b-c; b vs c |
| 0 | 0 (0.0%) | 5 (20.8%) | 15 (50.0%) | <0.001 a vs b-c |
| 1 | 2 (5.9%) | 17 (70.8%) | 11 (36.7%) | 0.030 b vs c |
| 2 | 12 (35.3%) | 2 (8.3%) | 3 (10.0%) | |
| 3 | 15 (44.1%) | 0 (0.0%) | 1 (3.3%) | |
| 4 | 5 (14.7%) | 0 (0.0%) | 0 (0.0%) | |
| n° cycles ATB | 2.50 ± 0.66 | 0.87 ± 0.54 | 0.47 ± 0.73 | <0.001 a vs b-c; b vs c |
| 0 | 0 (0.0%) | 5 (20.8%) | 19 (63.3%) | <0.001 a vs b-c |
| 1 | 2 (5.9%) | 17 (70.8%) | 9 (30.0%) | 0.002 b vs c |
| 2 | 14 (41.2%) | 2 (8.3%) | 1 (3.3%) | |
| 3 | 17 (50.0%) | 0 (0.0%) | 1 (3.3%) | |
| 4 | 1 (2.9%) | 0 (0.0%) | 0 (0.0%) | |
| WHO-5 (score 0-25) | 17.80 ± 1.40 | 21.4 ± 2.19 | <0.001 | |
| PGI-I (score 1-7) | 2.20 ± 0.41 | 4.05 ± 0.69 | <0.001 | |
| 1 | 0 (0.0%) | 0 (0.0%) | <0.001 | |
| 2 | 1 (4.2%) | 2 (6.7%) | ||
| 3 | 18 (75.0%) | 6 (20.0%) | ||
| 4 | 5 (20.8%) | 6 (20.0%) | ||
| 5 | 0 (0.0%) | 11 (36.7%) | ||
| 6 | 0 (0.0%) | 5 (16.7%) | ||
| 7 | 0 (0.0%) | 0 (0.0%) | ||
| Adverse Events | 0 | 0 |
| Fosfomycine Group | Nutraceutical Group | p-value | |||||
| Age, years | 62.9 ± 12.9 | 62.2 ± 16.0 | 0.942 | ||||
| BMI | 23.5 ± 3.0 | 27.2 ± 3.8 | <0.001 | ||||
| Smoke status | |||||||
| no | 24 (70.6%) | 42 (76.4%) | 0.621 | ||||
| yes | 10 (29.4%) | 13 (23.6%) | |||||
| Sexual activity | |||||||
| no | 15 (45.5%) | 26 (47.3%) | 0.999 | ||||
| yes | 18 (54.5%) | 29 (52.7%) | |||||
| Hormonal status | |||||||
| premenopausal | 4 (11.8%) | 13 (23.6%) | 0.267 | ||||
| postmenopausal | 30 (88.2%) | 42 (76.4%) | |||||
| Baseline (a) n= 34 | 3-months (b) n= 24 | 6-months (c) n= 30 | Baseline (d) n= 55 | 3-months (e) n= 55 | 6-months (f) n= 47 | ||
| n° UTI | 2.68 ± 0.81 | 0.87 ± 0.54 | 0.67 ± 0.80 | 1.87 ± 0.75 | 0.51 ± 0.63 | 0.28 ± 0.54 | 0.397 a vs d |
| 0.288 b vs e | |||||||
| 0.899 c vs f | |||||||
| n° cycles ATB | 2.50 ± 0.66 | 0.87 ± 0.54 | 0.47 ± 0.73 | 1.35 ± 0.98 | 0.49 ± 0.66 | 0.25 ± 0.53 | <0.001 a vs d |
| 0.558 b vs e | |||||||
| 0.883 c vs f | |||||||
| WHO-5 | 17.80 ± 1.40 | 21.4 ± 2.19 | 18.90 ± 3.91 | 20.2 ± 2.55 | 0.033 b vs e | ||
| (score 0-25) | |||||||
| 0.899 c vs f | |||||||
| PGI-I | 2.20 ± 0.41 | 4.05 ± 0.69 | 3.04 ± 1.61 | 2.43 ± 1.26 | 0.132 b vs e | ||
| (score 1-7) | |||||||
| 0.004 c vs f | |||||||
| Adverse Events | 0 (0.0%) | 0 (0.0%) | 2 (3.6%) | 1 (2.1%) | 0.999 |
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