Next Article in Journal
Polyphenols’ Impact on Selected Biomarkers of Brain Aging in Healthy Middle-Aged and Elderly Subjects: A Review of Clinical Trials
Previous Article in Journal
Untargeted Metabolomic Analysis of Lactation-Stage-Matched Human and Bovine Milk Samples at 2 Weeks Postnatal
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 15
Issue 17
10.3390/nu15173769
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of a Krill Oil, Astaxanthin, and Oral Hyaluronic Acid Complex on Joint Health in People with Mild Osteoarthritis

by
W. Stephen Hill
1,
Margaret H. Dohnalek
1,
Yejin Ha
2,
Seok-Jung Kim
3,
Jae-Chul Jung
2,* and
Seung-Baik Kang
4,*
1
US Nutraceuticals, Inc. d/b/a Valensa International, Eustis, FL 32726, USA
2
NOVAREX Co., Ltd., 80, Osongsaengmyeong 14-ro, Osong-eup, Chueongju-si 28220, Republic of Korea
3
Department of Orthopedic Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Cheonbo-ro, Uijeongbu-si 11765, Republic of Korea
4
Department of Orthopedic Surgery, Seoul National University College of Medicine, Boramae Hospital, Seoul 07061, Republic of Korea
*
Authors to whom correspondence should be addressed.
Nutrients 2023, 15(17), 3769; https://doi.org/10.3390/nu15173769
Submission received: 24 July 2023 / Revised: 14 August 2023 / Accepted: 21 August 2023 / Published: 29 August 2023
(This article belongs to the Section Clinical Nutrition)
Browse Figures
Versions Notes

Abstract

:
Osteoarthritis is a significant global health problem. Many patients seek more effective alternatives to nonsteroidal anti-inflammatory medicines or commercial supplements to manage joint pain and inflammation. FlexPro MD® (FP-MD) combines krill oil, astaxanthin, and lower molecular weight hyaluronic acid to support joint health. A 12-week, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of FP-MD and placebo once daily in participants (n = 100) with mild osteoarthritis of the knee or hip joint. For the primary endpoint of joint pain score, per-protocol participants (n = 75) in the FP-MD group (n = 37) had a statistically significantly greater mean reduction from baseline in the Korean Visual Analog Scale (K-VAS) at week 12 compared with participants in the placebo group (n = 38) (20.8 ± 16.16 mm vs. 10.6 ± 17.58, p = 0.0105). The Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC) total score was also significantly improved in the FP-MD group at week 12 compared with placebo (−13.0 ± 13.62 vs. −5.5 ± 18.08, p = 0.0489), especially an improvement in pain score (−2.5 ± 2.92 vs. −1.3 ± 3.94, p = 0.02635). FP-MD group had greater improvement in joint function scoring by investigator assessment (p = 0.0127) and by group participants (p = 0.0070). A statistically significantly greater number of patients reported adverse events in the placebo group compared with the FP-MD group (16% vs. 4%, p = 0.0455), most commonly gastrointestinal disorders in both of the groups. These findings suggest that FP-MD is well tolerated and can be effectively used to address joint pain in patients diagnosed with mild osteoarthritis, the main symptom of this condition.

1. Introduction

Arthritis is a chronic disease that affects millions of people worldwide. According to the Global Burden of Disease published in 2017, approximately 300 million people suffer from musculoskeletal disorders in 195 countries. Osteoarthritis and rheumatoid arthritis account for 19.3% and 1.3% of people affected by musculoskeletal disorders, respectively [1].
The global prevalence of osteoarthritis has increased by 48% from 1990 to 2019, with the highest prevalence in North America, specifically in people 50 to 60 years of age [2]. The pathogenesis of osteoarthritis is not uniform, and various causes have been reported. These include general factors such as age, sex, genetic reasons, and obesity, as well as external factors such as muscle weakness, leg length imbalance, and joint damage [3].
There is no cure for osteoarthritis, and most patients use a variety of treatment methods to relieve symptoms such as joint pain and stiffness. Medication treatments include oral acetaminophen, corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs), application of anti-inflammatory patches, or intraarticular injections of corticosteroid or hyaluronic acid (HA) to reduce inflammation and increase joint flexibility, respectively [4]. Physical therapies, such as diathermy, exercise therapy, and ultrasound therapy, are also used [5].
The most commonly used treatment for osteoarthritis is medication therapy, which aims to relieve pain and inflammation, improve joint function, and limit disease progression. Medication therapy should consider the patient’s underlying disease, other medications being taken, comorbidities, and patient preferences. Oral NSAIDs are the most commonly used medication to manage osteoarthritis. However, NSAID therapy can lead to various side effects, such as gastrointestinal tract disorders, cardiovascular issues, liver damage, and decreased renal function [6].
Interest in functional joint health ingredients with few side effects, such as soy isoflavones, N-acetylglucosamine, and methylsulfonylmethane (MSM), is increasing. These ingredients are known to regulate collagen degradation and synthesis, have anti-inflammatory activity, and inhibit joint damage by promoting cartilage synthesis [7,8,9]. FlexPro MD® (FP-MD) is a unique formulation of functional ingredients, specifically, omega-3 fatty acids (e.g., eicosapentaenoic [EPA] and docosahexaenoic acid [DHA]), astaxanthin, and a proprietary lower molecular weight HA. It is designed to address the root cause of joint breakdown and pain caused by oxidative stress. The FP-MD formulation delivers omega-3 fatty acids (e.g., EPA, DHA) in the form of krill oil to promote optimal omega-6:omega-3 ratios; a stable, easily absorbable, lipid-soluble antioxidant in the form of astaxanthin; and low molecular weight HA (500–50,000 Da) for improving joint lubrication. Of note, the phospholipid-bound omega-3 polyunsaturated fatty acids (PUFAs) in krill oil have been shown to improve the oral absorption of HA [10]. In addition, the oral bioavailability of astaxanthin is increased in the presence of emulsifiers, such as the phospholipids found in krill oil [11,12].
The objective of this study was to evaluate the efficacy and safety of FP-MD compared with a placebo in addressing joint pain in participants diagnosed with mild degenerative osteoarthritis after 12 weeks of supplementation.

2. Materials and Methods

2.1. Test Products

FlexPro MD® is a commercially available dietary supplement containing a combination of Euphausia superba Antarctic krill oil (321 mg, Superba®, Aker BioMarine Antarctic US LLC; Metuchen, NJ, USA), natural astaxanthin purified from Haematococcus pluvialis (2 mg, Zanthin® Natural Astaxanthin), and a proprietary HA produced from fermentation by Streptococcus zooepidemicus (30 mg, Flexonic® sodium hyaluronate (the sodium salt of HA), Valensa International; Eustis, FL, USA). FP-MD is a 600 mg soft capsule consisting of a reddish-brown, oily liquid. The placebo was an identically appearing soft capsule containing palm oil, olive oil, soybean oil, and beeswax (Table 1). Participants were instructed to take one capsule once daily for 12 weeks; no instructions were provided to take the capsule with or without food. Participants were also advised to maintain their regular diet and physical activity levels during the 12-week study period and not to consume other dietary sources of krill oil, Haematococcus (astaxanthin), or sodium hyaluronate. At the end of the study, the test product adherence rate was calculated as the number of capsules taken divided by the number of capsules dispensed ×100%.

2.2. Ethics

The study was conducted in accordance with the Declaration of Helsinki and approved by the respective Institutional Review Board (IRB) Research Ethics Review Committees of Boramae Hospital (IRB No. 30-2018-62) and Uijeongbu St. Mary’s Hospital (UIRB-New 2020092-013). All participants provided written informed consent before any screening assessment was completed. The study was retrospectively registered with the Clinical Trials Information Service (CRIS) of the Republic of Korea on 8 August 2023 (KCT0008749).

2.3. Participants and Eligibility Criteria

Participants for this clinical trial were recruited through online and offline advertisements for joint health. Korean men and women selected for inclusion were between the ages of 30 and 75 years with a Korean pain Visual Analog Scale (K-VAS) score of ≥30 mm [13] and Grade I or II for knee or hip joints based on the Kellgren and Lawrence scale for radiographic classification of osteoarthritis [14].
Potential participants were excluded if they had the following: (1) arthritis caused by specific factors other than degeneration as determined by the investigator; (2) joint spacing of ≤2 mm; (3) periarticular osteophyte phenomena, irregular articular surface, or subchondral bone cysts of the joints with moderate arthritis; (4) clinically significant cardiovascular, immune, infectious, and oncologic diseases; (5) concurrent treatment for gastritis or gastric ulcer; (6) uncontrolled hypertension (>160/100 mm Hg); (7) uncontrolled diabetes (fasting blood glucose > 180 mg/dL or starting a new diabetes medication within previous 3 months); (8) thyroid disease (thyroid stimulating hormone of <0.1 μU/mL or ≥10 μU/mL); (9) aspartate transaminase or alanine transaminase levels > 3 times the upper limit of normal; (10) creatinine level > 2 times the upper limit of normal; (11) pregnant or lactating women; (12) used arthritis-related medicines or dietary supplements within 2 weeks of screening; (13) mental illness (schizophrenia, depression, drug addiction, etc.); (14) received treatment for degenerative arthritis within 2 weeks of screening; (15) participated or planned to participate in other clinical trials within 2 months of baseline; (16) sensitivities or allergies to krill oil, astaxanthin, or HA; (17) been deemed inappropriate for study participation by the investigator.

2.4. Experimental Design

This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial of 93 participants who were randomized 1:1 to receive either an FP-MD or placebo soft gel once daily by mouth for 12 weeks. The random allocation sequence was generated by a randomization program of the SAS® system. In cases where participants violated the clinical trial protocol, such as failing to meet eligibility criteria, withdrawal of consent, non-adherence, or experiencing adverse events (AEs) that significantly impacted their safety or the study results, they were dropped after consultation with the investigator.

2.5. Primary Efficacy Assessment

The K-VAS is a highly reliable and valid tool for assessing joint pain that has been used in clinical trials [13,15]. Participants indicated their pain severity at 12 weeks using a 100 mm straight line, where 0 mm indicated no pain and 100 mm indicated unbearable pain.

2.6. Secondary Efficacy Assessments

2.6.1. K-VAS and Korean Medical Outcome Study 36-Item Short Form (KSF-36)

A change of K-VAS at 6 weeks was validated to check improvement of pain index during the middle of the dosage period. KSF-36 is the Korean version of the SF-36, a multidimensional generic health-related quality-of-life instrument consisting of 36 items. It is a general measurement tool that can measure overall health status, not targeting a specific age, disease condition, or treatment group. The KSF-36 score is expressed as a value between 0 (representing the lowest health status) and 100 (representing the highest health status) by converting the raw data.

2.6.2. Korean Western Ontario and McMaster Universities Osteoarthritis Index™ (K-WOMAC)

The WOMAC, a validated joint pain, stiffness, and physical function scale developed for patients with degenerative arthritis of the lower limb (e.g., knee and hip joints) [16], was adapted to Korean culture using a modified questionnaire. The K-WOMAC has been validated and used in various clinical trials [15,17,18]. Consistent with the WOMAC, the K-WOMAC has a total of 24 questions and consists of 3 subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). Each question is scored from 0 to 4, with lower scores indicating less pain or stiffness and better function. The K-WOMAC was assessed at baseline and weeks 6 and 12.

2.6.3. Serum C-Reactive Protein (CRP)

CRP is one of the plasma proteins that significantly increases in persons with inflammatory diseases or in the event of body tissue necrosis and is an acute phase protein. It has characteristics that cannot be observed in typical immunoglobulins, such as a rapid increase in levels within 6 to 24 h when a problem occurs in the body and a rapid decrease and disappearance within 24 h upon recovery. CRP data are very useful for determining the presence and severity of inflammatory or tissue-disrupting diseases as well as follow-up observations and determination of prognosis. It was measured at screening and week 12.

2.6.4. Urinary C-Telopeptide of Type II Collagen (CTX-II)

CTX-II is one of the major biomarkers for the evaluation of osteoarthritis, and the CTX-II is measured to determine the degree of cartilage wear using blood or urine [19]. About 10 mL of urine was collected at screening and week 12, stored frozen until the end of the clinical trial, and discarded after analysis at an external analysis agency.

2.6.5. Improvement Assessment

At weeks 6 and 12, participants and investigators assessed the degree of improvement compared with baseline using a 5-point improvement assessment score (Table 2). Participants completed this assessment without the investigator present and before the investigator’s assessment of improvement.

2.7. Safety Evaluations

Safety evaluations of test products included monitoring of AEs, conducting clinical pathology tests (e.g., hematologic, blood chemistry, blood lipid, and urine tests), measuring vital signs (e.g., pulse and blood pressure), checking physical measurements (body weight), and analyzing electrocardiogram results for abnormal findings throughout the study.
Adverse events were assessed throughout the study. Follow-up was conducted on all AEs until they disappeared, stabilized, or became definable symptoms.

2.8. Statistics

2.8.1. Sample Size

No formal statistical power analysis was completed to determine the study sample size. The enrollment goal was 50 participants per group to account for an expected dropout rate of 25%.

2.8.2. Analysis Sets

The per protocol (PP) set included all participants who completed the study and had no protocol violations. The safety set included all randomized participants who received at least one dose of test product.
Analysis of demographic and lifestyle data was based on the PP set. Efficacy analyses were based on the PP set to identify a treatment effect under optimal conditions. Safety analyses were based on the safety set.

2.8.3. Baseline Characteristics Analyses

Descriptive statistics were provided for demographic and lifestyle data, and comparisons between groups were made using the 2-sample t-test or Wilcoxon rank–sum test depending on the normality assumption. Categorical data were presented as frequencies and percentages for each level, and a Chi-square or Fisher exact test was used to test for independence.
Efficacy data were analyzed by calculating the mean and standard deviation using appropriate descriptive statistics. All tests of statistical significance were 2-tailed with alpha < 0.05. Analysis of covariance (ANCOVA) was used for efficacy endpoints to adjust for participant baseline characteristics.

2.8.4. Primary Efficacy Analysis

The change in mean K-VAS scores from baseline to week 12 was analyzed using a paired t-test or Wilcoxon signed–rank test according to whether normality was satisfied. To compare the changes between FP-MD and placebo groups, it was determined whether there was a statistically significant difference based on a 2-sample t-test or Wilcoxon rank–sum test based on ANCOVA and whether normality was satisfied.

2.8.5. Secondary Efficacy Analyses

Mean changes from baseline in the VAS at week 6 and the K-WOMAC total and subscale scores at weeks 6 and 12 were analyzed using a paired t-test or Wilcoxon signed–rank test according to whether normality was satisfied. To compare the changes between treatment groups, it was determined whether there was a statistically significant difference based on a 2-sample t-test or Wilcoxon rank–sum test based on ANCOVA and whether normality was satisfied. The participant and investigator improvement assessment scores were analyzed using a 2-sample t-test or a Wilcoxon rank–sum test depending on whether normality was satisfied.

2.8.6. Safety Analyses

The safety analysis evaluated the type and incidence of AEs, their severity, and their association with test products. Additionally, clinical pathology tests (hematologic, blood chemistry, and urine tests), vital signs (pulse, blood pressure), physical measurements (weight), and electrocardiogram test results were summarized descriptively. All AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA).
All statistical analyses were conducted using SAS (Version 9.4, SAS® Institute, Cary, NC, USA).

3. Results

This study was completed between 21 December 2018, and 25 October 2019, at two clinical sites in Korea. Of 105 people screened, 5 did not meet eligibility criteria, and 100 participants were randomized to FP-MD (n = 50) or placebo (n = 50) (safety set, Figure 1). In the FP-MD group, two withdrew consent or took concomitant prohibited medications. In the placebo group, 5 participants withdrew consent, experienced AEs, were lost to follow-up, violated eligibility criteria, or took concomitant prohibited medications, resulting in a total of 93 participants completing the clinical trial (FP-MD, n = 48; placebo, n = 45). Figure 1 shows the final PP set, along with the list of protocol violations.

3.1. Participant Characteristics

Table 3 shows a comparison of the participant baseline demographic and lifestyle characteristics. The FP-MD group had 16 men (43.2%) and 21 women (56.8%), whereas the placebo group had 15 men (39.5%) and 23 women (60.5%) (p = 0.7403). The mean age of both groups was similar (p = 0.2370). Further, there were no statistically significant differences between groups in exercise, smoking status, amount or duration, or alcohol consumption. There were no significant differences in baseline characteristics between groups; therefore, the comparability between groups was suitable for the evaluation of differences in efficacy and safety.

3.2. Joint Pain K-VAS

Mean joint pain K-VAS values were similar for the FP-MD and placebo groups at baseline (Table 4). For the primary efficacy endpoint (the difference between groups in the change in joint pain K-VAS scores from baseline to week 12), participants in the FP-MD group had a statistically significantly greater mean reduction in joint pain compared with participants in the placebo group (20.8 ± 16.16 mm vs. 10.6 ± 17.58, p = 0.0105 (unadjusted); p = 0.0255 (adjusted for baseline factors and adherence)) (Table 4, Figure 2).
For the secondary efficacy endpoint (the difference between groups from baseline to week 6 in the change in joint pain K-VAS scores), there was no statistically significant difference between groups (Table 4). The changes within groups from baseline to week 6 were statistically significant (FP-MD, 11.0 ± 12.62 mm (p < 0.0001); placebo, 8.1 ± 11.87 mm (p < 0.0001)).

3.3. K-WOMAC

Baseline K-WOMAC total and subscale scores were similar for FP-MD and placebo groups (Table 5). For the FP-MD group, within-group mean changes from baseline to weeks 6 and 12 were statistically significantly lower (improved) for the total K-WOMAC score and all subscale scores (p < 0.01 for all comparisons; Table 5). At week 12, the mean change from baseline in the total K-WOMAC score was statistically significantly lower in the FP-MD group compared with the placebo group (−13.0 ± 13.62 vs. −5.5 ± 18.08, p = 0.0489 (unadjusted); p = 0.1063 (adjusted for baseline factors and adherence)) (Figure 3).
Mean changes from baseline in the subscale scores were not statistically significantly different between FP-MD and placebo groups at week 6 (Table 5). However, at week 12, pain, stiffness, and physical function subscale scores were significantly lower in participants taking FP-MD (Table 5; Figure 3).

3.4. Investigator and Participant Improvement Assessment Scores

Both investigator and participant joint improvement assessment scores were statistically significantly lower, indicating a greater degree of improvement at weeks 6 and 12 (Table 6; Figure 4).

3.5. Serum CRP and Urinary CTX-II Levels

Analyses of changes in serum CRP and urinary CTX-II levels showed no statistically significant differences between FP-MD and placebo groups after 12 weeks of intake. Serum CRP level after 12 weeks of intake using the PP set showed a mean decrease of 0.04 ± 0.22 mg/dL (p = 0.7309 vs. baseline) for the FP-MD group and a mean increase of 0.02 ± 0.11 mg/dL (p = 0.8148 vs. baseline) for the placebo group, but there was no statistically significant difference between groups. Urinary CTX-II levels after 12 weeks of intake using the PP set showed a mean increase of 26.03 ± 280.22 ng/mmoL (p = 0.3972 vs. baseline) for the FP-MD group and a mean decrease of 66.33 ± 178.84 ng/mmoL (p = 0.0601 vs. baseline) for the placebo group, but there was no statistically significant difference between groups.

3.6. Safety Evaluation

Adverse events are summarized in Table 7. A statistically significantly greater number of patients reported AEs in the placebo group compared with the FP-MD group (16% vs. 4%, p = 0.0455). The most common AEs were gastrointestinal disorders in both the FP-MD (2%) and placebo groups (6%). Most AEs in both groups were mild or moderate; only one AE in the placebo group was rated as severe. All AEs were categorized by investigators as thought to be unrelated or clearly unrelated to test products. One serious AE (SAE) occurred in the FP-MD group (accidental injury requiring surgery) and two in the placebo group (pregnancy, intentional overdose of sleeping medication). No SAEs were thought to be related to test products. Only one participant dropped out of the study due to AEs, and this was in the placebo group.
Hematologic tests (Table S1), blood chemistry and lipid tests (Table S2), urine tests, vital signs (pulse, blood pressure) (Table S3), physical measurements (weight) (Table S3), and electrocardiogram analyses (Table S4) showed no statistically significant differences between the FP-MD and placebo groups during the 12-week study period.

4. Discussion

Osteoarthritis affects people of all ages, but it is more common in older individuals, affecting nearly half of adults over the age of 65. It is reported to be more prevalent in women than men and can be caused by various factors, including obesity, low mobility, and frequent intense exercise [14]. Arthritis severity is classified according to the Kellgren and Lawrence classification system, which includes five severity criteria (Grade 0: none, Grade 1: doubtful, Grade 2: minimal, Grade 3: moderate, Grade 4: severe) [20].
Most degenerative arthritis trials focus on participants with Kellgren and Lawrence severity between Grade 2 and Grade 3 [21,22]. However, this trial confirmed the efficacy of FP-MD as a dietary supplement in addressing the symptoms associated with joint pain and joint function in participants who presented with degenerative arthritis of Grade 1 or Grade 2 severity at screening. None of the patients in the FP-MD group had a worsening of their joint pain or joint function that would be associated with a possible progression of their degenerative arthritis. Compared with the placebo group, joint pain K-VAS scores and K-WOMAC total and subscale scores were significantly improved at week 12. These findings suggest that FP-MD intake for 12 weeks reduced joint pain and stiffness and improved physical function. In addition, statistically significant differences between FP-MD and placebo groups in the improvement assessment scores at both time points suggest investigators and participants recognized the effectiveness of taking FP-MD in alleviating arthritis symptoms as early as week 6.
Clinical research on natural product-based medicines and natural product ingredients for improving osteoarthritis is actively underway. Studies are being conducted on natural medicines that directly target specific mechanisms, such as arthritis inflammatory mechanisms (e.g., interleukin [IL-1], tumor necrosis factor [TNF]-α), cartilage mechanisms (e.g., Wnt signaling pathway, cathepsin-K, MMP/ADAMTS, growth hormone inhibitors), subchondral bone destruction, and pain reduction [23]. Furthermore, research on safe natural product medicines or dietary supplement ingredients using natural products is actively being carried out. Studies on joint pain indicators such as WOMAC and VAS have reported positive results after ingestion of functional ingredients such as Flavocoxid, Curcuma domestica, purple passion fruit peel, chicory root, Boswellia serrata, and Zingiber officinale as dietary supplements for up to 12 weeks [24].
Most studies have focused on evaluating the efficacy of a single substance, as previously noted, and there are few clinical trials confirming the synergistic effect of multiple compounds. Except for clinical trials confirming the synergistic effects of a blend of chondroitin, glucosamine, and MSM—representative natural supplements for degenerative arthritis—no clinical trials of more than three compounds have been identified. This highlights the need for further research on the synergistic effects of multiple compounds [25,26].
The main components of FP-MD are krill oil, astaxanthin, and HA, which have shown beneficial effects on joint health in both preclinical [27,28] and clinical studies [29]. Synergistic effects of these three ingredients have been shown in animal models induced by lipopolysaccharide (LPS) and monosodium iodoacetate (MIA). Krill oil, extracted from Euphausia superba in the Antarctic Ocean, contains phospholipid-bound omega-3 fatty acids, including EPA and DHA. Multiple preclinical studies have demonstrated the anti-inflammatory effects of omega-3 fatty acids and a reduction in joint pain [30,31]. A recent clinical trial of krill oil demonstrated significant improvements in knee pain, stiffness, and physical function as measured by the WOMAC in adults with mild to moderate knee osteoarthritis [32]. The Superba® krill oil used in FP-MD has undergone various studies to evaluate the extraction process, ingredient properties, and in vivo toxicity, confirming its safety and purity over many years [33,34,35].
Astaxanthin is a natural keto-carotenoid that exhibits molecular target activity in various diseases, including antioxidant, anticancer, antidiabetic, and protective effects in cardiovascular and neurologic diseases, as well as immunostimulating effects and is mainly purified from Haematococcus pluvialis and Phaffia rhodozyma [36]. The astaxanthin used in FP-MD was purified from Haematococcus pluvialis and has been shown in preclinical studies to reduce cartilage damage, prevent the progression of osteoarthritis, and have antioxidant effects [37,38]. Haematococcus pluvialis, a common source of astaxanthin, are freshwater microalgae that contain the highest natural concentration of natural astaxanthin [39]. An analysis of 328 reports of reported efficacy activity of astaxanthin supplements, particularly derived from Haematococcus, confirmed the greatest efficacy in sore muscles and joints (146 studies), back pain (48 studies), and osteoarthritis (20 studies), with 95% of osteoarthritis studies (19 of 20) reporting reduced pain and improved function [40].
Hyaluronic acid, isolated by Karl Meyer and John Palmer in 1934 [41], now plays a significant clinical role in several medical fields, including ophthalmology, joint pathology, skin repair, skin remodeling, vascular prosthesis, adipose tissue engineering, nerve reconstruction, and cancer treatment [42]. Hyaluronic acid, the most commonly prescribed natural ingredient for joint injections, has both lubricating and shock-absorbing properties in joints. Supplementation with injected HA fillers or oral administration of HA improves joint function by reducing inflammation in preclinical studies [43]. Clinical studies have also reported that intra-articular injections can improve joint mobility and reduce pain in patients with knee osteoarthritis [44]. Oral administration of HA has also been shown to improve clinical symptoms, including pain reduction, in clinical studies of patients with knee osteoarthritis [45,46,47]. The method of producing HA through Streptococcus zooepidemicus fermentation (the source of HA in FP-MD) began in 1997 [48,49] and has been studied in various ways to increase productivity [50,51]. The safety of HA has been demonstrated in multiple studies worldwide [52].
This 12-week intervention trial demonstrated that intake of FP-MD, a unique formulation of three synergistic ingredients (e.g., omega-3 fatty acids (EPA/DHA), astaxanthin, and lower molecular weight HA), can provide joint health benefits. The efficacy and safety profile in this study is consistent with the efficacy and safety reported in a previous study of FP-MD in a predominantly White population [29]. Although degenerative arthritis may have different specific causes and biological mechanisms, inflammation is a common feature of many forms of arthritis, and reduction in the pain caused by arthritis is an important part of arthritis treatment success [53].
Test product adherence and the occurrence of AEs are important indicators that can provide insight into the safety of raw materials in dietary supplements [54]. The rate of AEs in the FP-MD group was low and less than that of the placebo group. Overall, the high adherence rate, low AE rate, and lack of AE-related withdrawals in the FP-MD group indicate FP-MD is well tolerated.
As with all clinical trials, this study had several limitations. Although this study included only Korean participants, the results should be generalizable to other populations. The 12-week duration provided a reasonable time frame to assess FP-MD efficacy and safety; however, long-term studies are needed to demonstrate sustained effectiveness and provide additional safety data. Only participants with Kellgren and Lawrence Grade 1 or 2 osteoarthritis were evaluated; therefore, the effect of FP-MD on pain and physical function in individuals with moderate or severe degenerative arthritis is unknown.
This randomized controlled trial demonstrated statistically significant improvements in K-VAS pain scores and K-WOMAC total and subscale scores for participants taking FP-MD compared with placebo after 12 weeks of supplementation, confirming that this functional food can effectively address joint pain, the main symptom of degenerative arthritis, and improve physical function. Based on these clinical trial results and previously reported long-term safety data, the unique formulation of FP-MD, including krill oil, astaxanthin, and HA, is suggested as a dietary supplement to potentially reduce joint pain and improve physical function in individuals with mild osteoarthritis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu15173769/s1, Table S1: Hematologic Tests (Safety Set); Table S2: Blood Chemistry and Lipid Tests (Safety Set); Table S3: Vital Signs and Body Weight (Safety Set); Table S4: ECG Evaluation (Safety Set).

Author Contributions

Conceptualization, Y.H. and W.S.H.; methodology, S.-J.K. and S.-B.K.; validation, W.S.H., S.-J.K. and S.-B.K.; formal analysis, S.-B.K.; investigation, Y.H. and W.S.H.; resources, W.S.H.; data curation, S.-J.K., S.-B.K. and M.H.D.; writing—original draft preparation, Y.H.; writing—review and editing, W.S.H., M.H.D. and J.-C.J.; visualization, Y.H. and W.S.H.; supervision, J.-C.J. and S.-B.K.; project administration, S.-J.K. and S.-B.K.; funding acquisition, J.-C.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by a grant from the Ministry of Trade, Industry and Energy (MOTIE) through the Middle Market Enterprises Global Research R&D Project (R&D, P0000784) and World Class Plus Program (R&D, P0017150) supervised by the Korea Institute for Advancement of Technology (KIAT). NOVAREX Co., Ltd. funded the study. Valensa International provided the FlexPro MD® ingredients, and NOVAREX Co., Ltd. encapsulated the test products (e.g., both FlexPro MD® and placebo).

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the respective Institutional Review Board (IRB) Research Ethics Review Committees of Boramae Hospital (IRB No. 30-2018-62) and Uijeongbu St. Mary’s Hospital (UIRB-New 2020092-013).

Informed Consent Statement

Informed consent was obtained from all participants involved in the study.

Data Availability Statement

Data described in this study will be made available upon request pending application and approval from the corresponding author.

Acknowledgments

The authors thank NOVAREX Co., Ltd. in the Republic of Korea for funding the research, as well as Uijeongbu St. Mary’s Hospital and SMG–SNU Boramae Medical Center for conducting the clinical trial. We also thank the participants for their time and willingness to participate in the clinical trial. Editing and formatting assistance was provided by Dana L. Randall, Intuitive Graphite, Inc., and funded by US Nutraceuticals, Inc. d/b/a Valensa International.

Conflicts of Interest

NOVAREX Co., Ltd. funded the study. Valensa International provided the FlexPro MD® ingredients, and NOVAREX Co., Ltd. encapsulated the test products (e.g., both FlexPro MD® and placebo). All authors were also involved in the design of the study; the collection, analyses, and interpretation of data; the writing of the manuscript; and in the decision to publish the results. The authors declare no other conflicts of interest in the present research or publishing of the data.

References

  1. Safiri, S.; Kolahi, A.A.; Cross, M.; Hill, C.; Smith, E.; Carson-Chahhoud, K.; Mansournia, M.A.; Almasi-Hashiani, A.; Ashrafi-Asgarabad, A.; Kaufman, J.; et al. Prevalence, Deaths, and Disability-Adjusted Life Years Due to Musculoskeletal Disorders for 195 Countries and Territories 1990–2017. Arthritis Rheumatol. 2021, 73, 702–714. [Google Scholar] [CrossRef] [PubMed]
  2. Safiri, S.; Kolahi, A.A.; Smith, E.; Hill, C.; Bettampadi, D.; Mansournia, M.A.; Hoy, D.; Ashrafi-Asgarabad, A.; Sepidarkish, M.; Almasi-Hashiani, A.; et al. Global, regional and national burden of osteoarthritis 1990–2017: A systematic analysis of the Global Burden of Disease Study 2017. Ann. Rheum. Dis. 2020, 79, 819–828. [Google Scholar] [CrossRef] [PubMed]
  3. Zhang, Y.; Jordan, J.M. Epidemiology of osteoarthritis. Clin. Geriatr. Med. 2010, 26, 355–369. [Google Scholar] [CrossRef]
  4. Kolasinski, S.L.; Neogi, T.; Hochberg, M.C.; Oatis, C.; Guyatt, G.; Block, J.; Callahan, L.; Copenhaver, C.; Dodge, C.; Felson, D.; et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020, 72, 220–233. [Google Scholar] [CrossRef] [PubMed]
  5. Berteau, J.P. Knee Pain from Osteoarthritis: Pathogenesis, Risk Factors, and Recent Evidence on Physical Therapy Interventions. J. Clin. Med. 2022, 11, 3252. [Google Scholar] [CrossRef]
  6. Sinusas, K. Osteoarthritis: Diagnosis and treatment. Am. Fam. Physician 2012, 85, 49–56. [Google Scholar]
  7. Debbi, E.M.; Agar, G.; Fichman, G.; Ziv, Y.B.; Kardosh, R.; Halperin, N.; Elbaz, A.; Beer, Y.; Debi, R. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: A randomized controlled study. BMC Complement. Altern. Med. 2011, 11, 50. [Google Scholar] [CrossRef]
  8. Wei, P.; Liu, M.; Chen, Y.; Chen, D.C. Systematic review of soy isoflavone supplements on osteoporosis in women. Asian Pac. J. Trop. Med. 2012, 5, 243–248. [Google Scholar] [CrossRef]
  9. Tomonaga, A.; Watanabe, K.; Fukagawa, M.; Suzuki, A.; Kurokawa, M.; Nagaoka, I. Evaluation of the effect of N-acetyl-glucosamine administration on biomarkers for cartilage metabolism in healthy individuals without symptoms of arthritis: A randomized double-blind placebo-controlled clinical study. Exp. Ther. Med. 2016, 12, 1481–1489. [Google Scholar] [CrossRef]
  10. Huang, S.L.; Ling, P.X.; Zhang, T.M. Oral absorption of hyaluronic acid and phospholipids complexes in rats. World J. Gastroenterol. 2007, 13, 945–949. [Google Scholar] [CrossRef]
  11. Mercke Odeberg, J.; Lignell, A.; Pettersson, A.; Höglund, P. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. Eur. J. Pharm. Sci. 2003, 19, 299–304. [Google Scholar] [CrossRef] [PubMed]
  12. Park, J.S.; Chyun, J.H.; Kim, Y.K.; Line, L.L.; Chew, B.P. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutr. Metab. 2010, 7, 18. [Google Scholar] [CrossRef]
  13. Kim, D.Y.; Lee, S.H.; Lee, H.Y.; Lee, H.J.; Chang, S.B.; Chung, S.K.; Kim, H.J. Validation of the Korean version of the oswestry disability index. Spine 2005, 30, E123–E127. [Google Scholar] [CrossRef]
  14. Kellgren, J.H.; Lawrence, J.S. Radiological assessment of osteo-arthrosis. Ann. Rheum. Dis. 1957, 16, 494–502. [Google Scholar] [CrossRef] [PubMed]
  15. Kim, G.J.; Oh, H.; Lee, S.; Lee, K.; Kim, K. Effects of resistance exercise using the elastic band on the pain and function of patients with degenerative knee arthritis. J. Phys. Ther. Sci. 2020, 32, 52–54. [Google Scholar] [CrossRef] [PubMed]
  16. Jinks, C.; Jordan, K.; Croft, P. Measuring the population impact of knee pain and disability with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain 2002, 100, 55–64. [Google Scholar] [CrossRef]
  17. Bae, S.C.; Lee, H.S.; Yun, H.R.; Kim, T.H.; Yoo, D.H.; Kim, S.Y. Cross-cultural adaptation and validation of Korean Western Ontario and McMaster Universities (WOMAC) and Lequesne osteoarthritis indices for clinical research. Osteoarthr. Cartil. 2001, 9, 746–750. [Google Scholar] [CrossRef]
  18. Kim, T.H.; Kim, K.H.; Kang, J.W.; Lee, M.; Kang, K.W.; Kim, J.E.; Kim, J.H.; Lee, S.; Shin, M.S.; Jung, S.Y.; et al. Moxibustion treatment for knee osteoarthritis: A multi-centre, non-blinded, randomised controlled trial on the effectiveness and safety of the moxibustion treatment versus usual care in knee osteoarthritis patients. PLoS ONE 2014, 9, e101973. [Google Scholar] [CrossRef]
  19. Garnero, P.; Peterfy, C.; Zaim, S.; Schoenharting, M. Bone marrow abnormalities on magnetic resonance imaging are associated with type II collagen degradation in knee osteoarthritis: A three-month longitudinal study. Arthritis Rheum. 2005, 52, 2822–2829. [Google Scholar] [CrossRef]
  20. Hawker, G.A. Osteoarthritis is a serious disease. Clin. Exp. Rheumatol. 2019, 37 (Suppl. S120), 3–6. [Google Scholar]
  21. Kare, S.K.; Vinay, V.; Maresz, K.; Prisk, V.; Vik, H. Tamarindus indica Seed Extract-Based Botanical Compositions Alleviate Knee Pain and Improve Joint Function in Mild-to-Moderate Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Clinical Study. Evid. Based Complement. Alternat Med. 2022, 2022, 2226139. [Google Scholar] [CrossRef]
  22. Kohn, M.D.; Sassoon, A.A.; Fernando, N.D. Classifications in Brief: Kellgren-Lawrence Classification of Osteoarthritis. Clin. Orthop. Relat. Res. 2016, 474, 1886–1893. [Google Scholar] [CrossRef]
  23. Cai, X.; Yuan, S.; Zeng, Y.; Wang, C.; Yu, N.; Ding, C. New Trends in Pharmacological Treatments for Osteoarthritis. Front. Pharmacol. 2021, 12, 645842. [Google Scholar] [CrossRef] [PubMed]
  24. Walzer, S.M.; Weinmann, D.; Toegel, S. Medical Plant Extracts for Treating Knee Osteoarthritis: A Snapshot of Recent Clinical Trials and Their Biological Background. Curr. Rheumatol. Rep. 2015, 17, 54. [Google Scholar] [CrossRef] [PubMed]
  25. Lubis, A.M.T.; Siagian, C.; Wonggokusuma, E.; Marsetyo, A.F.; Setyohadi, B. Comparison of Glucosamine-Chondroitin Sulfate with and without Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial. Acta Med. Indones. 2017, 49, 105–111. [Google Scholar] [PubMed]
  26. Sawitzke, A.D.; Shi, H.; Finco, M.F.; Dunlop, D.D.; Harris, C.L.; Singer, N.G.; Bradley, J.D.; Silver, D.; Jackson, C.G.; Lane, N.E.; et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann. Rheum. Dis. 2010, 69, 1459–1464. [Google Scholar] [CrossRef]
  27. Park, D.R.; Ko, R.; Kwon, S.H.; Min, B.; Yun, S.H.; Kim, M.H.; Minatelli, J.; Hill, S.; Lee, S.Y. FlexPro MD, a Mixture of Krill Oil, Astaxanthin, and Hyaluronic Acid, Suppresses Lipopolysaccharide-Induced Inflammatory Cytokine Production Through Inhibition of NF-κB. J. Med. Food 2016, 19, 1196–1203. [Google Scholar] [CrossRef]
  28. Park, M.H.; Jung, J.C.; Hill, S.; Cartwright, E.; Dohnalek, M.H.; Yu, M.; Jun, H.J.; Han, S.B.; Hong, J.T.; Son, D.J. FlexPro MD®, a Combination of Krill Oil, Astaxanthin and Hyaluronic Acid, Reduces Pain Behavior and Inhibits Inflammatory Response in Monosodium Iodoacetate-Induced Osteoarthritis in Rats. Nutrients 2020, 12, 956. [Google Scholar] [CrossRef]
  29. Dohnalek, M.H.; Cartwright, E.J.; Hill, W.S. Efficacy and Safety of a Joint Health Nutritional Supplement for Subjects with Non-arthritic Knee Joint Pain: A Double-blind, Placebo- and Active-Controlled, Randomized Clinical Trial. J. Orthop. Res. Ther. 2023, 8, 1272. [Google Scholar] [CrossRef]
  30. Wann, A.K.; Mistry, J.; Blain, E.J.; Michael-Titus, A.T.; Knight, M.M. Eicosapentaenoic acid and docosahexaenoic acid reduce interleukin-1β-mediated cartilage degradation. Arthritis Res. Ther. 2010, 12, R207. [Google Scholar] [CrossRef]
  31. Lim, J.Y.; Park, C.K.; Hwang, S.W. Biological Roles of Resolvins and Related Substances in the Resolution of Pain. Biomed. Res. Int. 2015, 2015, 830930. [Google Scholar] [CrossRef]
  32. Stonehouse, W.; Benassi-Evans, B.; Bednarz, J.; Vincent, A.D.; Hall, S.; Hill, C.L. Krill oil improved osteoarthritic knee pain in adults with mild to moderate knee osteoarthritis: A 6-month multicenter, randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr. 2022, 116, 672–685. [Google Scholar] [CrossRef] [PubMed]
  33. Gigliotti, J.C.; Davenport, M.P.; Beamer, S.K.; Tou, J.C.; Jaczynski, J. Extraction and characterisation of lipids from Antarctic krill (Euphausia superba). Food Chem. 2011, 125, 1028–1036. [Google Scholar] [CrossRef]
  34. Berge, K.; Robertson, B.; Burri, L. Safety assessment of Superba™ krill powder: Subchronic toxicity study in rats. Toxicol. Rep. 2015, 2, 144–151. [Google Scholar] [CrossRef] [PubMed]
  35. Robertson, B.; Burri, L.; Berge, K. Genotoxicity test and subchronic toxicity study with Superba™ krill oil in rats. Toxicol. Rep. 2014, 1, 764–776. [Google Scholar] [CrossRef]
  36. Ambati, R.R.; Phang, S.M.; Ravi, S.; Aswathanarayana, R.G. Astaxanthin: Sources, extraction, stability, biological activities and its commercial applications—A review. Mar. Drugs 2014, 12, 128–152. [Google Scholar] [CrossRef] [PubMed]
  37. Ohgami, K.; Shiratori, K.; Kotake, S.; Nishida, T.; Mizuki, N.; Yazawa, K.; Ohno, S. Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Investig. Ophthalmol. Vis. Sci. 2003, 44, 2694–2701. [Google Scholar] [CrossRef]
  38. Speranza, L.; Pesce, M.; Patruno, A.; Franceschelli, S.; Lutiis, M.A.; Grilli, A.; Felaco, M. Astaxanthin treatment reduced oxidative induced pro-inflammatory cytokines secretion in U937: SHP-1 as a novel biological target. Mar. Drugs 2012, 10, 890–899. [Google Scholar] [CrossRef]
  39. Stachowiak, B.; Szulc, P. Astaxanthin for the Food Industry. Molecules 2021, 26, 2666. [Google Scholar] [CrossRef]
  40. Guerin, M.; Huntley, M.E.; Olaizola, M. Haematococcus astaxanthin: Applications for human health and nutrition. Trends Biotechnol. 2003, 21, 210–216. [Google Scholar] [CrossRef]
  41. Meyer, K.; Palmer, J.W. The Polysaccharide of the Vitreous Humor. J. Biol. Chem. 1934, 107, 629–634. [Google Scholar] [CrossRef]
  42. Abatangelo, G.; Vindigni, V.; Avruscio, G.; Pandis, L.; Brun, P. Hyaluronic Acid: Redefining Its Role. Cells 2020, 9, 1743. [Google Scholar] [CrossRef] [PubMed]
  43. Zhou, P.H.; Liu, S.Q.; Peng, H. The effect of hyaluronic acid on IL-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis. J. Orthop. Res. 2008, 26, 1643–1648. [Google Scholar] [CrossRef] [PubMed]
  44. Moreland, L.W. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: Mechanisms of action. Arthritis Res. Ther. 2003, 5, 54–67. [Google Scholar] [CrossRef]
  45. Tashiro, T.; Seino, S.; Sato, T.; Matsuoka, R.; Masuda, Y.; Fukui, N. Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: A double-blind, placebo-controlled study over a 12-month period. Sci. World J. 2012, 2012, 167928. [Google Scholar] [CrossRef]
  46. Nelson, F.R.; Zvirbulis, R.A.; Zonca, B.; Li, K.W.; Turner, S.M.; Pasierb, M.; Wilton, P.; Martinez-Puig, D.; Wu, W. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol. Int. 2015, 35, 43–52. [Google Scholar] [CrossRef]
  47. Ricci, M.; Micheloni, G.M.; Berti, M.; Perusi, F.; Sambugaro, E.; Vecchini, E.; Magnan, B. Clinical comparison of oral administration and viscosupplementation of hyaluronic acid (HA) in early knee osteoarthritis. Musculoskelet. Surg. 2017, 101, 45–49. [Google Scholar] [CrossRef]
  48. Armstrong, D.C.; Cooney, M.J.; Johns, M.R. Growth and amino acid requirements of hyaluronic-acid-producing Streptococcus zooepidemicus. Appl. Microbiol. Biotechnol. 1997, 47, 309–312. [Google Scholar] [CrossRef]
  49. Armstrong, D.C.; Johns, M.R. Culture Conditions Affect the Molecular Weight Properties of Hyaluronic Acid Produced by Streptococcus zooepidemicus. Appl. Environ. Microbiol. 1997, 63, 2759–2764. [Google Scholar] [CrossRef]
  50. Flores-Gatica, M.; Castañeda-Aponte, H.; Gil-Garzon, M.R.; Mora-Galvez, L.M.; Banda-Magaña, M.P.; Jáuregui-Jáuregui, J.A.; Torres-Acosta, M.A.; Mayolo-Deloisa, K.; Licona-Cassani, C. Primary recovery of hyaluronic acid produced in Streptococcus equi subsp. zooepidemicus using PEG-citrate aqueous two-phase systems. AMB Express 2021, 11, 123. [Google Scholar] [CrossRef]
  51. Wang, J.; He, W.; Wang, T.; Li, M.; Li, X. Sucrose-modified iron nanoparticles for highly efficient microbial production of hyaluronic acid by Streptococcus zooepidemicus. Colloids Surf. B Biointerfaces 2021, 205, 111854. [Google Scholar] [CrossRef] [PubMed]
  52. Oe, M.; Tashiro, T.; Yoshida, H.; Nishiyama, H.; Masuda, Y.; Maruyama, K.; Koikeda, T.; Maruya, R.; Fukui, N. Oral hyaluronan relieves knee pain: A review. Nutr. J. 2016, 15, 11. [Google Scholar] [CrossRef] [PubMed]
  53. Cubukcu, D.; Sarsan, A.; Alkan, H. Relationships between Pain, Function and Radiographic Findings in Osteoarthritis of the Knee: A Cross-Sectional Study. Arthritis 2012, 2012, 984060. [Google Scholar] [CrossRef] [PubMed]
  54. Ezzelle, J.; Rodriguez-Chavez, I.R.; Darden, J.M.; Stirewalt, M.; Kunwar, N.; Hitchcock, R.; Walter, T.; D’Souza, M.P. Guidelines on good clinical laboratory practice: Bridging operations between research and clinical research laboratories. J. Pharm. Biomed. Anal. 2008, 46, 18–29. [Google Scholar] [CrossRef]
Nutrients 15 03769 g001
Figure 1. Consolidated Standards of Reporting Trial (CONSORT) participant disposition diagram for the per-protocol set. FP-MD, FlexPro MD®.
Figure 1. Consolidated Standards of Reporting Trial (CONSORT) participant disposition diagram for the per-protocol set. FP-MD, FlexPro MD®.
Nutrients 15 03769 g001
Nutrients 15 03769 g002
Figure 2. Effect of FP-MD on VAS score at weeks 6 and 12. FP-MD, FlexPro MD®; VAS, Visual Analog Scale. * p-value based on 2-sample t-test.
Figure 2. Effect of FP-MD on VAS score at weeks 6 and 12. FP-MD, FlexPro MD®; VAS, Visual Analog Scale. * p-value based on 2-sample t-test.
Nutrients 15 03769 g002
Nutrients 15 03769 g003
Figure 3. Changes in K-WOMAC score after 12 weeks of FP-MD intake compared with placebo. FP-MD, FlexPro MD®; K-WOMAC, Korean Western Ontario and McMaster Universities Osteoarthritis Index. * p-value based on 2-sample t-test. † p-value based on Wilcoxon rank–sum test.
Figure 3. Changes in K-WOMAC score after 12 weeks of FP-MD intake compared with placebo. FP-MD, FlexPro MD®; K-WOMAC, Korean Western Ontario and McMaster Universities Osteoarthritis Index. * p-value based on 2-sample t-test. † p-value based on Wilcoxon rank–sum test.
Nutrients 15 03769 g003
Nutrients 15 03769 g004
Figure 4. Effects of oral intake of FlexPro MD® (FP-MD) on joint improvement assessment score evaluation by investigator and participants at weeks 6 and 12 compared with placebo. * p-value based on Wilcoxon rank–sum test.
Figure 4. Effects of oral intake of FlexPro MD® (FP-MD) on joint improvement assessment score evaluation by investigator and participants at weeks 6 and 12 compared with placebo. * p-value based on Wilcoxon rank–sum test.
Nutrients 15 03769 g004
Table 1. Composition of FP-MD and placebo capsules.
Table 1. Composition of FP-MD and placebo capsules.
CompositionFP-MD 600 mg
mg (%)		Placebo 600 mg
mg (%)
FP-MD462 (77)0
Antarctic krill oil321 (53.5)0
Haematococcus pluvialis extract
(to deliver 2 mg astaxanthin)		25–35 (4–5)0
Sodium hyaluronate33 (5.5)0
Excipients73–83 (12–14) *
Palm oil0400 (67)
Olive oil062 (10)
Soybean oil114 (19)114 (19)
Beeswax24 (4)24 (4)
* Amount (mg) depends on quantity of Haematococcus pluvialis extract.
Table 2. Improvement assessment score.
Table 2. Improvement assessment score.
ScoreDegreeSymptoms
1Much betterSignificant improvement in symptoms
2BetterOverall improvement of symptoms
3No changeNo difference from baseline
4WorseOverall worsening of symptoms
5WorsenSignificant worsening of symptoms
Table 3. Participant baseline demographic and lifestyle characteristics (per protocol set).
Table 3. Participant baseline demographic and lifestyle characteristics (per protocol set).
FP-MD
n = 37		Placebo
n = 38		Total
n = 75		p-Value
Sex
n (%)		Male16 (43.24)15 (39.47)31 (41.33)0.7403 †
Female21 (56.76)23 (60.53)44 (58.67)
Age
(y)		Mean ± SD57.0 ± 10.2859.0 ± 11.8258.0 ± 11.060.2370 &
Min, Max31.0, 70.035.0, 75.031.0, 75.0
Exercise frequency (%)None7 (18.9)6 (15.8)13 (17.3)0.9100 †
<3 sessions/week or <30 min/session15 (40.5)15 (39.5)30 (40.00)
≥3 sessions/week or >30 min/session15 (40.5)17 (44.7)32 (42.7)
Smoking status
n (%)		Non-smoker31 (83.8)32 (84.2)63 (84.0)0.1569 ‡
Ex-smoker
Stopped smoking > 6 months before screening visit		03 (7.9)3 (4.0)
Smoker6 (16.2)3 (7.9)9 (12.0)
Cigarettes/day
(among smokers)		Mean ± SD11.7 ± 4.0811.7 ± 7.611.7 ± 5.00.8774 &
Min, max10.0, 20.05.0, 20.05.0, 20.0
Smoking (years)
(among smokers)		Mean ± SD26.0 ± 9.3821.7 ± 7.6424.6 ± 8.620.5141 *
Min, max10.0, 36.015.0, 30.010.0, 36.0
Alcohol
consumption
n (%)		None22 (59.5)20 (52.6)42 (56.0)0.5829 ‡
Quit1 (2.7)1 (2.6)2 (2.7)
<1 bottle/week5 (13.5)10 (26.3)15 (20.0)
1~2 bottles/week7 (18.9)4 (10.5)11 (14.7)
>3 bottles/weeks2 (5.4)3 (7.9)5 (6.7)
Body height
(cm)		Mean ± SD161.9 ± 10.24160.8 ± 9.74161.4 ± 9.940.6259 &
Min, max145.2, 184.1145.1, 180.0145.1, 184.1
* Compared between groups; p-value based on 2-sample t-test. & Compared between groups; p-value based on Wilcoxon rank–sum test. † Compared within groups; p-value based on Chi-square test. ‡ Compared within groups; p-value based on Fisher exact test.
Table 4. K-VAS scores (per protocol set).
Table 4. K-VAS scores (per protocol set).
K-VAS (mm)FP-MD
(n = 37)		Placebo
(n = 38)		p-Valuep-Value ‡
Mean ± SDMean ± SD
Baseline46.1 ± 9.7742.7 ± 8.380.1596 †
Week 635.1 ± 17.1334.6 ± 16.490.1059 †0.0854
Change from baseline−11.0 ± 12.62−8.1 ± 11.87
p-value<0.0001 **<0.0001 #
Week 1225.3 ± 16.3932.1 ± 19.080.0105 *0.0255
Change from baseline−20.8 ± 16.16−10.6 ± 17.58
p value **<0.00010.0007
* Compared between groups; p-value based on 2-sample t-test. † Compared between groups; p-value based on Wilcoxon rank–sum test. ** Compared within groups; p-value based on paired t-test. # Compared within groups; p-value based on Wilcoxon signed–rank test. ‡ Compared between groups; p-value based on ANCOVA adjusted by baseline and adherence.
Table 5. K-WOMAC total and subscales scores (per protocol set).
Table 5. K-WOMAC total and subscales scores (per protocol set).
FP-MD
(n = 38)		Placebo
(n = 37)		p-Valuep-Value ‡
Mean ± SDMean ± SD
  • Total score
Baseline30.7 ± 14.8128.3 ± 13.550.4737 *
Week 621.2 ± 13.1023.5 ± 13.750.1304 *0.1658
Change from baseline−9.5 ± 12.57−4.8 ± 14.10
p-value **<0.00010.0432
Week 1217.7 ± 15.0622.8 ± 15.070.0489 *0.1063
Change from baseline−13.0 ± 13.62−5.5 ± 18.08
p-value **<0.00010.0674
2.
Pain score
Baseline6.0 ± 3.225.7 ± 2.640.6582 †
Week 64.0 ± 2.744.7 ± 2.980.1675 *0.1149
Change from baseline−2.0 ± 3.14−1.0 ± 6.07
p-value **0.00040.0518
Week 123.5 ± 2.994.5 ± 3.450.02635 †0.1779
Change from baseline−2.5 ± 2.92−1.3 ± 3.94
p-value<0.0001 **0.0173 #
3.
Stiffness score
Baseline2.9 ± 1.612.3 ± 1.440.5240 †
Week 62.0 ± 1.312.1 ± 1.350.4294 †0.0854
Change from baseline−0.9 ± 1.78−0.5 ± 1.45
p-value0.0040 #0.0310 **
Week 121.8 ± 1.572.0 ± 1.620.2819 †0.0255
Change from baseline−1.1 ± 2.08−0.6 ± 1.79
p-value0.0039 **0.0282 #
4.
Physical function score
Baseline21.8 ± 11.0320.0 ± 10.250.4639 *
Week 615.2 ± 9.8416.1 ± 10.140.1528 *0.2148
Change from baseline−6.6 ± 9.25−3.3 ± 10.80
p-value **0.00010.0705
Week 1212.4 ± 10.8316.3 ± 10.860.0398 *0.0890
Change from baseline−9.4 ± 9.99−3.7 ± 13.38
p-value **<0.00010.1005
* Compared between groups; p-value based on 2-sample t-test. † Compared between groups; p-value based on Wilcoxon rank–sum test. ** Compared within groups; p-value based on paired t-test. # Compared within groups; p-value based on Wilcoxon signed–rank test. ‡ Compared between groups; p-value based on ANCOVA adjusted by baseline factors and adherence.
Table 6. Investigator and participant improvement assessment scores (per protocol set).
Table 6. Investigator and participant improvement assessment scores (per protocol set).
FP-MD
(n = 37)		Placebo
(n = 38)		p-Value †
Mean ± SDMean ± SD
Investigator assessment score
Week 62.4 ± 0.682.7 ± 0.530.0238
Week 122.1 ± 0.742.5 ± 0.720.0127
Participant assessment score
Week 62.4 ± 0.652.7 ± 0.450.0194
Week 122.1 ± 0.702.6 ± 0.800.0070
† Compared between groups; p-value based on Wilcoxon rank–sum test.
Table 7. Summary of adverse events (safety set).
Table 7. Summary of adverse events (safety set).
FP-MD
(n = 50)		Placebo
(n = 50)		p-Value
nIncidence (%)CasesnIncidence (%)Cases
Adverse events (AEs)24.02816.0100.0455 †
Serious AEs (SAE)12.0124.021.0000 ‡
Dropouts due to AEs00.0012.011.0000 ‡
† p-value based on Chi-square test. ‡ p-value based on Fisher exact test.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Hill, W.S.; Dohnalek, M.H.; Ha, Y.; Kim, S.-J.; Jung, J.-C.; Kang, S.-B. A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of a Krill Oil, Astaxanthin, and Oral Hyaluronic Acid Complex on Joint Health in People with Mild Osteoarthritis. Nutrients 2023, 15, 3769. https://doi.org/10.3390/nu15173769

AMA Style

Hill WS, Dohnalek MH, Ha Y, Kim S-J, Jung J-C, Kang S-B. A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of a Krill Oil, Astaxanthin, and Oral Hyaluronic Acid Complex on Joint Health in People with Mild Osteoarthritis. Nutrients. 2023; 15(17):3769. https://doi.org/10.3390/nu15173769

Chicago/Turabian Style

Hill, W. Stephen, Margaret H. Dohnalek, Yejin Ha, Seok-Jung Kim, Jae-Chul Jung, and Seung-Baik Kang. 2023. "A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of a Krill Oil, Astaxanthin, and Oral Hyaluronic Acid Complex on Joint Health in People with Mild Osteoarthritis" Nutrients 15, no. 17: 3769. https://doi.org/10.3390/nu15173769

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop