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Henrotin et al. BMC Musculoskeletal Disorders https://doi.org/10.1186/s12891-022-05612-2
(2022) 23:650
Open Access
RESEARCH Rubus idaeus extract improves symptoms in knee osteoarthritis patients: results from a phase II double‑blind randomized controlled trial Yves Henrotin 1,2,3* , Romain Le Cozannet 4 , Pascale Fança‑Berthon 4 , Romain Truillet 5 , Martine Cohen‑Solhal 6 , Gillian DunnGalvin 7 , Jean‑Marie Grouin 8 and Andrea Doolan 7 Abstract Background: Osteoarthritis (OA) is the most frequent cause of disability in elderly people. In daily practice, the main objective of the physician is to reduce patient symptoms using treatments without adverse effects. However, the most prescribed treatment to manage OA symptoms remains nonsteroidal anti-inflammatory drugs which are associated with severe adverse effects. Therefore, we need a safe alternative to managing OA. One candidate is Rubus idaeus leaf extracts known to inhibit inflammatory responses. Objective: This study aimed to evaluate the effects of a 12-weeks intervention with an ethanolic extract from Rubus idaeus leaf on symptoms of knee osteoarthritis. Method: The study was a randomized, double-blind, placebo-controlled, monocentric trial of 198 participants with femorotibial osteoarthritis. Participants were randomized equally to receive one daily during 3 months either 1 capsule of Rubus idaeus leaf extract 400 mg, 1 capsule of Rubus idaeus leaf extract 200 mg, or 1 capsule of placebo. The participants were assessed at baseline and after one and three months of treatment. The primary endpoint was an absolute change of the Western Ontario McMaster osteoarthritis index (WOMAC) pain subscale. The secondary endpoints were WOMAC global score, stiffness and function sub-scales, knee pain VAS score at walking, the Short Form (SF)-36, the Short Physical Performance Battery (SPPB), the 20-m walk test, and the International Physical Activ‑ ity Questionnaire (IPAQ) and Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) responders rate. Statistical analyses were conducted on the intent-to-treat (ITT) population. Results: In the Intention-to-treat population, WOMAC pain was not significantly modified by Rubus idaeus leaf extract compared to placebo. In contrast, Rubus idaeus leaf extract 400 mg after 12 weeks of treatment significantly reduced pain measured by the VAS. The mean pain decrease induced by Rubus ideaus leaf extract was over -7 mm which is clinically relevant and reached a clinically statistical difference compared to placebo with the highest dose.
*Correspondence: yhenrotin@uliege.be 1 musculoSKeletal Innovative Research Lab (mSKIL), The Center
for Interdisciplinary Research On Medicines (CIRM), Department of Motricity Center, Institute of Pathology, University of Liège, CHU Sart-Tilman, level 5, 4000 Liège, Belgium Full list of author information is available at the end of the article
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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Rubus Ideaus was not significantly more efficient than the placebo on WOMAC global score, stiffness, and physical function subscores, IPAQ, SF-36, walking distance in treadmill test, SPPB, and evaluation of associated treatments needed to manage OA. Conclusion: Rubus idaeus leaf extract was well tolerated and effective to relieve pain in a patient with knee osteoarthritis. Trial registration: NCT03703024 (11/10/2018). Keywords: Osteoarthritis, Knee, Rubus idaeus, Pain, Clinical trial
Introduction Osteoarthritis (OA) is the major cause of disability in older adults. In the USA, Federal Drug Administration (FDA) has recognized that OA can be a serious disease for which no pharmacological treatment can modify the underlying pathophysiology of the disease and change its natural course [1]. Currently, patient management aims to reduce symptoms and improve quality of life using therapeutic modalities with low side effects. Recently, the Osteoarthritis Research Society International (OARSI) recommended patient education, physical activities including exercise programs, and weight control with diet intervention as the core treatment for all patients what- ever their health status and OA severity [2]. Pharmaco- logical modalities can be associated with core treatment if the core treatment alone is not satisfying or to facilitate patients’ adhesion to exercise programs. Among these pharmacological modalities, the use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) was recommended in well-defined conditions while opioids and paraceta- mol were no more recommended. Therefore, there is a need for safe treatments with an efficacy supported by well-conducted clinical trials. One safe approach could be nutraceuticals for which the most used to manage joint discomfort are glucosamine, chondroitin, collagen, Boswellia, and turmeric extracts [3]. Another potential candidate is Rubus idaeus (Raspberry) leaf extract (RIE) rich in flavonoids and phenols that are known to inhibit inflammatory responses [4] by preventing the activa- tion of MAPK or NFkB signaling pathways [5]. Moreo- ver, polyphenolic-enriched red raspberry Rubus fruit extract reduces collagen breakdown in bovine chondro- cytes as well as the severity of arthritis in an antigen- induced arthritis rat model [6]. In cartilage explants, RIE prevented the loss of proteoglycan and MMP-3 and MMP-13 protein expressions. RIE reduced the expres- sion of interleukin (IL)-1 and -6 in macrophages, without change in Tumor Necrosis Factor (TNF) and cyclooxyge- nase (Cox)-2 expression. The secretome of macrophages pre-treated with RIE and transferred in chondrocytes decreased the gene expression and protein synthesis of MMP-3, -13, and Cox-2. Globally, these in vitro stud- ies suggested that RIE could limit synovitis and prevent
cartilage degradation without inducing toxicity [4]. Pat- ented data (US20200222486A1) demonstrated that RIE increased the secretion of 5-HETE and 12-HETE, two intermediaries of the lipoxygenase pathway involved in the resolution of inflammation-induced in mice by injec- tion of methylated bovine serum albumin (mBSA). In this model, Rubus Idaeus extract decreased the level of circu- lating IL-6 plasma but increased the level of 12-HETE, as well as reduced joint swelling in paws [7]. No toxic effects of the investigational product have been reported. In this paper, we report the effect of RIE, on symp- toms impairing the quality of life in people suffering from OA. Thus, we conducted a randomized, double-blinded, placebo-controlled trial to assess whether supplemen- tation with RIE improved OA knee pain and function. This study was the first trial applied to the human body. Further, this phase II study has been conducted in full accordance with the International Council for Harmo- nisation of Technical Requirements for Pharmaceuticals for Human use (ICHE6) that examined the impact of ingesting a food supplement composed of RIE on allevi- ating pain, function, and physical performance in elderly participants who reported having mild to moderate knee pain. Population and design Study design This study was a phase II randomized, double-blind, pla- cebo-controlled with three parallel groups and a mono- centric trial including 195 patients with a primary knee OA. Participants were recruited from June 1, 2017, to December 31, 2018. The main inclusion criteria were an age of 30 to 75 years, a Body Mass Index (BMI) between 18.5 and 35 kg/m 2 , a documented diagnosis of primary OA of the target knee made at least 12 months before screening, radiographic evidence of OA in the tibiofemoral com- partment of the target knee with at least one osteophyte and a measurable joint space narrowing, as diagnosed by standard X-rays taken no longer than 18 months, and a mild to moderate pain not adequately or completely controlled with NSAIDs. The most painful knee was considered the target knee. The main exclusion criteria
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function ranging from 0 to 68 subscales, and the partici- pant global assessment of the quality of life using a short form (SF) survey of 36 questions, the International Physi- cal Activity Questionnaire (IPAQ) expressed as MET-min per week, the 20-m walking speed, the Short Physical Per- formance Battery (SPPB) including gait speed measured over 3 m, chair stand time, and standing balance evalu- ation, the evaluation of associated treatments needed to manage OA and the Outcome Measures in Rheu- matology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) respond- ers rate. The OMERACT–OARSI criteria for response are (1) improvement in pain or physical function ≥ 50% and an absolute change ≥ 20 mm; or (2) improvement of ≥ 20% with an absolute change ≥ 10 mm in pain and physical function. Compliance with the study treatments was established by counting unused study products. All variables were recorded at baseline, after 6 weeks and 12 weeks of treatment. Determination of the sample size A prior power calculation was used to determine the sample size in this trial. To determine the appropriate sample size a literature review was completed. The anal- ysis of different nutraceutical medication studies with a similar primary endpoint in the OA population showed a significant response to treatment using a group size of an average of n = 45 patients [8, 9]. Taking this informa- tion into consideration a sample size of 60 patients/group ( n = 180) was chosen to be more than adequate to meet sample size requirements defined for a decrease of 14% of the WOMAC scores taking into account a drop-out rate of 7–9% for a treatment period of 3 months, an α of 0.05 and a β of 0.20 (power of 80%). With an expected 8% drop-out rate, it was decided that 65 participants were to be randomized into each group. Statistical analysis Statistical analyses were conducted by using SAS ver- sion 9.4 (SAS Institute, Cary, NC) on the intent-to-treat (ITT) population, which included all participants who were randomized into the study, and consumed at least one dose of the study product. Between-group assess- ments at baseline were evaluated by one-way-analysis-of- variance (ANOVA) for continuous data and Chi-Square for independence for categorical data. In a posthoc analy- sis, participants with BMI < 25 or ≥ 25 kg/m 2 have been compared. The cut-off of 25 was selected because over this value the patient fell within the overweight or obese range. Change from baseline was used for comparisons. Change scores were evaluated by mixed-model repeated- measures analysis containing the treatment group, the visit, the baseline score of dependent outcomes, and the
were pregnancy or lactation, secondary knee OA, a Kell- gren-Lawrence grade IV in the patellofemoral compart- ment of the target knee, a clinically objective effusion of the target knee or other joint, asymptomatic OA of the contralateral knee that was not responsive to paraceta- mol and required other therapy, change of dietary habit within the preceding month, allergy or contraindication to the tested product, a concurrent medical or psychi- atric condition that, in the opinion of the investigator, could have compromised patient’s ability to comply with the study requirements, use of viscosupplementation in any joint including the target knee or other joint within 9 months before screening. Calcium or other dietary sup- plements in the last months were also exclusion criteria. Participants enrolled could have taken paracetamol and/ or oral NSAIDs to manage knee pain. Participants were then asked to use these rescue medications only when needed during the trial. Twenty-four hours before a visit, participants were asked to stop rescue medication for the evaluation of clinical parameters by the investigator. The trial has been conducted following the Good Clinical Practices (GCP) guidelines and according to the "Decla- ration of Helsinki" published by the World Medical Asso- ciation. The study protocol was approved by the Central Ethics Committee of The University College Cork, Irland (namely Clinical Research Ethics Committee), agreement number: ECM 4 (I) 07/02/17. This RCT was also registered on Clinical trial.gov on NCT03703024 https://clinicaltrials.gov/ct2/show/ NCT03703024 (first registration date 11/10/2018). Treatment assignment The participants were randomly assigned to one of the study groups. They received one daily each morning for 12 weeks either 1 capsule containing 400 mg of RIE or 1 capsule containing 200 mg of RIE or 1 capsule of pla- cebo. RIE was a natural hydro-alcoholic extract produced from the leaves of Rubus Idaeus accordingly to patent US20200222486A1. The RIE was standardized in poly- phenols such as sanguiine H6 (C82H54O52; molar mass: 1871.27 g / mol) which is one of the main active ingredi- ents. The placebo capsules contained 100% maltodextrin. Outcome measures The primary outcome was changed, if any, in pain scores in the target knee joint from baseline to the end of treatment using WOMAC Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) pain subscale with a possi- ble score range between 0 to 20.The secondary outcomes were pain change using the VAS (Visual Analogue Scale), change in the WOMAC global (sum of each WOMAC subscale) or stiffness ranging from 0 to 8 and physical
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withdrawn due to receiving a clinically abnormal blood result, and one participant was withdrawn due to a lack of study product, and two participants did not give rea- sons for their withdrawal. All other 198 participants completed the study as planned (Fig. 1). Two hundred three participants were included in the Safety population as they took at least one dose of the product, 198 participants were considered eligi- ble for the ITT analysis. Among the Safety population, 68 participants received a placebo, 69 RIE 200 mg, and 66 RIE 400 mg. The number of withdrawals was 2 in the placebo group, 2 in the RIE 200 mg group, and 5 in the 400 mg group (Fig. 1; Additional file 1). At baseline, participants in each group were well-matched (Table 1). Females and males were equally distributed among the three groups. 68.7% in RIE 400 mg, 74.3% in RIE 200 mg, and 70.6% of placebo participants were overweight or obese (BMI ≥ 25 kg/m2). All participants had a diagno- sis of OA. 53% had a Kellgren-Lawrence score of 1 and 38% had a Kellgren-Lawrence score of 2. The remaining
treatment x visit interaction. The adequacy of the model was verified by residuals analysis. Normality distribution of the residuals was verified by Skewness and Kurtosis (less than 2 in absolute value). Data presented were the mean and standard error model (SEM). All tests of sig- nificance were completed at α = 0.05, two-tailed. Dun- nett corrections were performed to adjust the p-value for multiple comparisons (active treatment group versus a placebo group). Results Population A total of 208 participants (74 men and 124 female) were randomly assigned to treatment on a 1:1:1 basis, where n = 70 participants were allocated to the Placebo arm, n = 69 participants were allocated to the 200 mg RIE arm, and n = 69 participants were allocated to the 400 mg RIE arm. Nine participants withdrew prematurely from the study, five of these were withdrawn due to an adverse event/Severe Adverse Event (SAE), one participant was
Fig. 1 Flow diagram of RUBUS study
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Table 1 Demographic and baseline characteristics (ITT population N = 198)) Placebo ( N = 68) 200 mg ( N = 66)
400 mg ( N = .64)
All ( N = 198)
P -values
Sex
n/n miss
68/0
66/0
64/0
198/0
0.52
Male, n(%)
25 (36.8%) 43(63.2%%)
28(42.4%) 38(57.6.%)
21(32.8%) 43 (67.2%)
74 (37.4%) 124 (62.6%)
Female, n(%)
Ethnicity
n/n miss
68/0
66/0
64/0
198/0
0.37
Asian, n(%) African, n(%)
0(0.0%) 0 (0.0%)
1(1.5%%)
0 (0.0%) 0 (0.0%)
1 (0.5%%)
0(0.0%)
0 (0.0%)
Caucasian, n(%)
68(100.0%)
65 (98.5%)
64 (100.0%)
197(99.5%)
Age (years)
n/n miss
68/0
66/0
64/0
198/0
0.21
Mean (SEM)
52.93 (1.39)
55.71 (1.21)
55.69 (1.25)
54.75 (0.75)
Median Min, Max n/n miss
52.50
54.50
56.60
55.00
30.0, 74.0
31.0, 75.0
35.0, 74.0
30.0, 75.0
BMI (kg/m 2 )
68/0
66/0
64/0
198/0
Mean (SEM)
27.16 (0.40)
26.70 (0.36)
26.88 (0.41)
26.92 (0.22)
Median Min, Max
27.49
26.60
26.49
26.69
0.70
20.10, 32.20 20 (29.4%) 32 (47.1%) 16 (23.5%)
19.96, 31.83 17 (25.8%) 38 (57.6%) 11 (16.7%)
19.06, 33.88 20 (31.3%) 31 (48.4%) 13(20.3%)
19.06, 33.88 57 (28.8%) 101 (51.0%) 40 (20.2%)
Normal [18.5—25[ Overweigth [25–30[ Obese ≥ 30
WOMAC global
n/n miss
68/0
66/0
64/0
198/0
0.81
Mean (SEM)
24.43 (1.68)
25.84(1.47)
24.80(1.58)
25.02 (0.91)
Median Min, Max n/n miss
20.83
26.04
23.44
22.92
3.1, 63.5
4.2, 55.2
6.3,56.3
3.1, 63.5
WOMAC pain
68/0
66/0
64/0
198/0
0.64
Mean (SEM)
4.66 (0.34)
5.14 (0.38)
4.87 (0.36)
4.89 (0.21)
Median Min, Max n/n miss
4.00
5.00
4.00
4.00
1.0, 14.0
0.0, 16.0
1.0, 12.0
0.0, 16.0
WOMAC stiffness
68/0
66/0
64/0
198/0
0.94
Mean (SEM)
2.71 (0.19)
2.77 (0.17)
2.78 (0.16)
2.75 (0.10)
Median Min, Max n/n miss
3.00
3.00
3.00
3.00
0.0, 6.0
0.0, 7.0
0.0, 5.0
0.0, 7.0 198/0
WOMAC function
68/0
66/0
64/0
0.86
Mean (SEM)
16.09 (1.19)
16.89 (1.02)
16.16 (1.18)
16.38 (0.65)
Median Min, Max n/n miss
13.00
17.00
15.00
15.00
2.0, 43.0
2.0, 39.0
1.0, 41.0
1.0, 43.0
VAS pain
68/0
66/0
64/0
198/0
0.97
Mean (SEM)
40.28 (2.15)
40.95 (2.29)
40.75 (2.04)
40.66 (1.24)
Median Min, Max n/n miss
40.00
40.00
40.00
40.00
10.0, 85.0
5.0, 80.0
10.0, 80.0
5.0, 85.0
SF36
67/1
66/0
64/0
197/1
0.68
Mean (SEM)
54.48 (17.90)
53.79 (20.68)
54.30 (19.70)
54.19 (19.35)
Median Min, Max
50.00
50.00
50.00
50.00
25.0, 100.0
25.0, 100.0
25.0, 100.0
25.0, 100.0
Walking test 20 m (s) n/n miss
68/0
66/0
64/0
198/0
0.51
Mean (SEM)
14.29 (0.25)
14.65 (0.22)
14.58 (0.22)
14.50 (0.14)
Median Min, Max
14.06
14.31
14.54
14.27
8.8, 22.2
11.3, 20.2
11.1, 19.9
8.8, 22.2
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Table 1 (continued)
Placebo ( N = 68) 200 mg ( N = 66)
400 mg ( N = .64)
All ( N = 198)
P -values
SPPB
n/n miss
68/0
66/0
64/0
198/0
0.26
Mean (SEM)
10.50 (0.15)
10.36 (0.15)
10.70 (0.14)
10.52 (0.08)
Median
11.00
10.00
11.00
11.00
Min, Max n/n miss
8.0,12.0
6.0, 12.0
9.0, 12.00
6.0, 12.0
IPAQ
64/4
63/3
64/0
193/7
0.71
Mean (SEM)
2711.58 (400.61)
2996.67 (509.16) 3251.88 (472.38) 2986.66 (266.05)
Median Min, Max
1623.00
1332.00
1721.50
1428.00
99.0, 19,640.0
0.0, 23,640.0
198.00,17,695.0 0.0, 23,640.0
BMI Body Mass Index, WOMAC Western Ontarion McMaster osteoarthritis index, VAS Visual analog scale, SF-36 Short Form (36), SPPB Short Physical Performance Battery, IPAQ International Physical Activity Questionnaire. Baseline differences assessed by one-way-analysis-of variance for continuous data, and Pearson’s Chi Square for categorical data
participants (9%) had a Kellgren-Lawrence score of 3. No significant differences were observed between the three treatment groups according to demographic character- istics and BMI. Fifty-one participants had a BMI < 25 kg/ m2 and 147 had a BMI ≥ 25. At baseline, global WOMAC and subscores, VAS pain, SF-36, SPPB, and IPAQ scores were not significantly different between BMI groups (Additional file 2). Clinical outcomes In ITT population, WOMAC pain (in mean (SEM) at baseline: 4.89 (0.21)) significantly decreased over time in all groups ( p < 0.0001). However, there was no differ- ence between treatments. RIE 200 mg and 400 mg after
12 weeks of treatment reduced pain measured by the VAS respectively of -8.51 (1.92) mm and -10.93 (1.95) mm compared to baseline, while the placebo group had a -3.84 (1.89) mm reduction. This means pain reduc- tion induced by RIE reached a statistical difference com- pared to placebo at the highest dose (-7.09 (2.71); 95% CI, -13.11 to -1.07; p = 0,017) (Fig. 2, Table 2). At the daily dosage of 200 mg or 400 mg, the effect size calculated on the VAS pain score of the ITT population was 0.30 and 0.45 after 12 weeks, respectively. After 12 weeks of treatment, a subgroup analysis of the participants with a BMI ≥ 25, highlighted VAS pain reduction for the 200 and 400 mg doses compared to baseline of respectively -11.25 (2.14) mm and -13.36
Fig. 2 Time evolution of the VAS pain score in ITT population. * = significant effect of RIE 400 mg compared to placebo
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Table 2 Primary and secondary outcomes – Absolute change from baseline in ITT population 6 Weeks 12 Weeks Placebo RIE 200 mg RIE 400 mg Placebo
RIE 200 mg RIE400 mg
WOMAC Pain (primary outcome)
Mean (SE) 95% CI
1.29 (0.31) -1.89; -0.68 < 0.0001 -5.60 (1.52) -8.58; -2.62 0.0002 -0.48 (0.17) -0.81; -0.14 0.0052 --3.60 (1.08) --5.72; -1.49 0.0009 -5.12 (1.89) -8.83; -1.42 0.0068
-1.91 (0.31) -2.52; -1.29 < 0.0001 0.2718 -7.28 (1.54) -10.31; -4.25 < 0.0001 0.6573 -0.79 (0.17) -1.13; -0.45 < 0.0001 0.3299 -4.30 (1.09) -6.45; -2.16 < 0.0001 0.8609 -9.22 (1.92) -12.99; -5.46 < 0.0001 0.2223 4.55 (19.07) -50.00, 75.00 0.9761 -0.41 (1.75) -4.0, 7.6 0.9391 0.26 (1.23) -2.0, 6.0 0.9996
-1.79 (0.32) -2.41; -1.16 < 0.0001 0.4199 -7.66 (1.57) -10.73; -4.59 < 0.0001 0.5416 -0.95 (0.17) -1.29; -0.60 < 0.0001 0.0970 -4.61 (1.11) -6.79; -2.44 < 0.0001 0.7301 -5.32 (1.95) -9.15; -1.50 -1.17 (16.32) -50.00, 50.00 0.0544 -0.36 (1.75) -6.7, 3.5 0.9838 0.0064 0.9960
-1.98 (0.31) -2.59; -1.36 < 0.0001 -10.22 (1.54) -13.25; -7.20 < 0.0001 -1.14 (0.17 -1.47; -0.80 < 0.0001 -6.69 (1.09) -8.84; -4.55 < 0.0001 -3.84 (1.89) -7.55; -0.14 0.0421
-2.01 (0.31) -2.63; -1.40 < 0.0001 0.9955 -9.41 (1.54) -12.44; -6.38 < 0.0001 0.9036 -1.08 (0.17) -1.41; -0.74 < 0.0001 0.9587 -5.95 (1.09) -8.10; -3.81 < 0.0001 0.8480 -8.51 (1.92) -12.27; -4.75 < 0.0001 0.1485 2.27 (21.36) -50.00, 50.00 0.9785 -0.39 (1.69) -4.5, 3.0 0.9349 0.39 (1.37) -4.0, 6.0 1.0000 37.48 (216.29) -94.3, 1339.4 0.9601
-2.46 (0.32) -3.09; -1.84 < 0.0001 0.4517 -11.29 (1.57) -14.36; -8.21 < 0.0001 0.8441 -1.01 (0.17) -1.35; -0.67 < 0.0001 0.8310 -7.36 (1.11) -9.54; -5.19 < 0.0001 0.8742 -10.93 (1.95) -14.76; -7.11 < 0.0001 0.0176 3.13 (20.65) -50.00, 50.00 0.9212 -0.30 (1.94) -6.9, 3.8 0.9724 0.22 (0.81) -3.0, 2.0 0.6386 36.62 (184.88) -96.5, 1052.0 0.9950
P value vs baseline P value vs placebo
WOMAC global
Mean (SE) 95% CI
P value vs baseline P value vs placebo
WOMAC stiffness
Mean (SE) 95% CI
P value vs baseline P value vs placebo
WOMAC function
Mean (SE) 95% CI
P value vs baseline P value vs placebo
VAS pain
Mean (SE) 95% CI
P value vs baseline P value vs placebo Mean (SD) Min., Max P value vs placebo Mean (SD) Min., Max P value vs placebo Mean (SD) Min., Max P value vs placebo Mean (SD) Min., Max P value vs placebo
SF-36
5.97 (16.91) -25.00, 50.00
2.61 (19.04) -50.00, 50.00
20 m walking test
-0.31 (1.30) -4.1, 3.2
-0.18 (1.53) -4.2, 4.2
SPPB
0.21 (0.86) -2.0, 2.0
0.05 (0.72) -2.0, 2.0 0.5601
0.34 (0.94) -2.0, 2.0
IPAQ
107.48 (298.81) -90.2, 1693.8
173.08 (560.57) -100.0, 3400.0 0.9493
102.46 (279.33) -89.6, 1300.0 0.9306
38.38 (275.67) -95.0, 2000.0
RIE had no significant effect on the other second- ary end-points (IPAQ, SF-36, walking distance in tread- mill test, SPPB, and evaluation of associated treatments needed to manage OA) except for the IPAQ score at 400 mg in the normal BMI group at 12 weeks ( p = 0.017). After 12 weeks of treatment, over 60% of patients ful- filled the OMERACT-OARSI criteria in RIE 400 mg group, but only 45% in the placebo ( p = 0.04) (Fig. 4). There were two not-related-to-product Serious Adverse Events (SAE) reported in this study. One partici- pant had a severe SAE as they were diagnosed with pros- tate cancer. This participant was withdrawn from the trial due to SAE after visit 1. The other participant had a mod- erate SAE due to renal calculus. This participant recov- ered within three days and remained in the trial. There were 123 AEs reported by 87 (42.9%) partici- pants in total for the Safety Population ( N = 203). In addi- tion, 95.1% of AEs were mild to moderate intensity. There were 29 participants (42.6%) in the placebo group who reported ≥ 1 AE(s), 32 participants (46.4%) in the RIE 200 mg group who reported ≥ 1 AEs, and 26 participants
(2.26) mm (placebo = -0.37 (2,16) mm). The reduc- tion was statistically different versus placebo for both doses (200 mg -10.88 (3.04); 95% CI, -17.64 to -4.12 p = 0.0008 and 400 mg -12.99 (3.13); 95% CI, -19.95 to -6.04 p < 0,0001) (Fig. 3). No significant effect of RIE was observed in the normal BMI group. The WOMAC global score, stiffness, and physical func- tion subscores decreased significantly with time in all groups. The decrease tended to be more important in the RIE treated groups than in the placebo groups but no significant difference between groups was observed (Table 2). RIE at 400 mg was significantly more efficient than placebo to decrease the WOMAC stiffness score in the normal BMI group after 6, but not 12 weeks of treat- ment (p = 0.042). In the normal BMI group, a higher decrease in the WOMAC pain, physical function, and global scores were observed in the RIE 200 mg group than in the placebo group after 6 weeks of treatment (WOMAC global pain: p = 0.007742; WOMAC physical function: p = 0.0027; WOMAC global: p = 0.0026) (Addi- tional file 3).
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Fig. 3 Time evolution of VAS pain in the participant of the ITT population with a Body Mass Index (BMI) > to 25. * = significant effect of RIE compared to placebo
Fig. 4 Percentage of participants of the ITT population responding to treatment according to OMERACT-OARSI criteria. * = significant effect of RIE compared to placebo
and eight participants (12.1%) in the RIE 400 mg who reported ≥ 1 AEs possibly-related-to-product. Only one participant in each active product group had reported two possibly-related-to-product AEs. Eight (33.3%) of the possibly-related-to-product AEs ( N = 24) were due to elevated blood results requiring General Practitioner follow-up reported by eight participants ( N = 2 Pla- cebo; N = 4 RIE 200 mg group; N = 2 RIE 400 mg group). Twelve (50.0%) possibly-related-to-product AEs ( N = 24)
(39.4%) in the RIE 400 mg, who reported ≥ 1 AE(s). How- ever, there were only 22 participants (10.8%) with ≥ 1 AEs possibly-related-to-product in the Safety Population ( N = 203) who reported a total of 24 AEs possibly-related- to-product. All other AEs reported were identified as not related-to-product. There were four participants (5.9%) in the placebo group who reported 1 AE possibly-related -to-product, ten participants (14.5%) in the RIE 200 mg group who reported ≥ 1 AEs possibly-related-to-product,
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rescue medication use. For those with data, 61.0% (Total N = 108; Placebo N = 33; Active product N = 75) took no rescue medication before baseline to the end of the study, and 22.0% (Total N = 39; Placebo N = 15; Active product N = 24) reduced their use of rescue medication, 13.6% (Total N = 24; Placebo N = 11; Active product N = 13) increased their use of rescue medication and 3.4% (Total N = 6; Placebo N = 3; Active product N = 3) used the rescue medication at the same frequency that at base- line and week 12. The active product group (either dose) attended to have a higher ratio (61.5%; N = 24) of reduc- ing their rescue medication use compared to the placebo (38.5%; N = 15). Discussion In this paper, we report the data of a clinical trial investigating the clinical efficacy of two doses of RIE, administered orally for 3 months in patients with symptomatic established knee OA. Compared to pla- cebo, RIE was not effective on the WOMAC pain which was the primary end-point. In contrast, RIE sig- nificantly and rapidly relieved pain evaluated by VAS in knee OA patients. At the daily dosage of 200 mg or 400 mg, the effect size calculated on the VAS pain score of the ITT population was 0.30 and 0.45 after 12 weeks, respectively. Compared to NSAIDs and par- acetamol, the effect size for the pain of RIE is compa- rable. Indeed, a meta-analysis has reported effect sizes for pain compared to oral placebo comprised between 0.38 and 0.52 for NSAIDs after 12 weeks of treatment [10]. Comparing to paracetamol (ES: 0.18 (0.04 to
were due to gastrointestinal issues reported by ten par- ticipants ( N = 1 Placebo; N = 5 RIE 200 mg group; N = 4 RIE 400 mg group) where three participants had to dis- continue the study due to diarrhea. One of these AEs (RIE 400 mg) was deemed severe for epigastric pain (RIE 400 mg) but this had resolved within one day with no reoccurrence. Two (8.3%) were due to skin rashes ( N = 2 RIE 400 mg group). The two remaining AEs were a severe AE for a swollen knee (RIE 400 mg) and an AE (Placebo) for Deep Vein Thrombosis which occurred after a flight abroad. In sum, there were no SAEs related to the product and there was a low proportion of related-to-product AEs in either active product group. In addition, the overall pat- tern of safety blood panel and vitals results from baseline to end of the intervention indicated no safety concerns. The product can be viewed as tolerable as only 2.2% ( N = 3) of the active product groups ( N = 135) had to dis- continue the product due to gastrointestinal AE. In total, 191 participants returned their product by end of the trial and the population had high study product compliance and adherence to protocol. Of the partici- pants who returned the product, 185 (96.9%) had a study product consumption compliance equal to or greater than 80%. The mean compliance was 95.96% (SD 7.12, Min 57.0%, max 110.0%). Rescue medication use was recorded in the daily e-diary app as an exploratory outcome. This analy- sis focused on the week before baseline and week 12 (Table 3). Due to missing data, 21 participants from the ITT population were not included in the analysis for
Table 3 Rescue Medication Use the week prior to baseline and end of intervention in the ITT population for participants with available data ( N = 177) N %
Placebo ( N = 62)
No medication use at either Week 0 or Week 12 Medication use reduces from Week 0 to Week 12 Medication use increases from Week 0 to Week 12 No change between Week 0 and Week 12 No medication used at either Week 0 or Week 12 Medication use reduces from Week 0 to Week 12 Medication use increases from Week 0 to Week 12 No change between Week 0 and Week 12 No medication used at either Week 0 or Week 12 Medication use reduces from Week 0 to Week 12 Medication use increases from Week 0 to Week 12 No change between Week 0 and Week 12 No medication used at either Week 0 or Week 12 Medication use reduces from Week 0 to Week 12 Medication use increases from Week 0 to Week 12 No change between Week 0 and Week 12
33 15 11
53.2% 24.2% 17.7%
3
4.8%
Treatment (200 dose) ( N = 59)
43 11
72.9% 18.6%
2 3
3.4% 5.1%
Treatment (400 dose) ( N = 56)
32 13 11
57.1% 23.2% 19.6%
0
0.0%
Treatment ( N = 115)
75 24 13
65.2% 20.9% 11.3%
3
2.6%
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Conclusions This randomized controlled clinical trial demonstrated that RIE, a rubus ideaus extract, is a safe and efficient treatment to manage symptoms of patients with knee OA. Of course, this result needs to be confirmed in a larger phase III clinical trial including not only clinical parameters but also biochemical markers of inflamma- tion and cartilage degradation and imaging structural analysis of joint tissues. This trial provides useful infor- mation for the design of a larger phase III clinical trial including the sample size estimate, the choice of the dose, and the selection of primary outcomes. Abbreviations AE: Adverse effect; BMI: Body Mass Index; COX: Cyclooxygenase; ES: Effect Size; HETE: Hydroxyeicosatetraenoic acids; IPAQ: International Physical Activ‑ ity Questionnaire; ITT: Intention-To-Treat; MAPK: Mitogen-activated protein kinases; MET: Metabolic Equivalent of Task; MMP: Matrix MetalloProteinase; NFKB: Nuclear Factor-Kappa B; NSAIDs: Nonsteroidal Anti-inflammatory Drugs; OA: Osteoarthritis; OARSI: Osteoarthritis Research Society International; OMERACT: Outcome Measures in Rheumatology; RIE: Rubaeus Ideaus Extract; SEM: Standard Error of Mean; SF-36: Short Form (36); SPPB: Short Physical Performance Battery; VAS: Visual Analog Scale; WOMAC: Western Ontario McMaster osteoarthritis index. Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s12891-022-05612-2. Additional file 1. Listing 1. By Participant Listing Of Analysis Sets. Additional file 2. Comparison of demographic and clinical outcomes atbaseline between normal BMI and overweight/obese BMI group in the ITTpopulation ( N = 198). Additional file 3. Absolute change from baselinein normal BMI group. Additional file 4. Absolute change from baseline in BMI ≥ 25group.
0.33), RIE was even more efficient [10]. Considering the excellent safety of RIE, this extract could be a good alternative to NSAIDs and paracetamol that show severe adverse effects after long-term administration. Further, our study demonstrated that RIE treatment was associated with a greater reduction of rescue med- ications including paracetamol and NSAIDS than pla- cebo. This data again indicates that RIE has an antalgic effect superior to that of paracetamol and NSAIDs. A feature of this study was that it included participants with mild to moderate pain not adequately or com- pletely controlled with NSAIDs. This finding indicates that RIE is efficient where NSAIDS are not. This could be explained by the difference in the mechanisms of action. NSAIDs act on inflammation mainly by inhibit- ing cyclooxygenases while RIE acts by preventing the activation of MAPK or NFkB signaling pathways that lead to the secretion of a large panel of pro-inflam- matory cytokines and metalloproteases [3] as well as on the resolution of the inflammation. We can spec- ulate that in some participants RIE mechanisms of action are more appropriate to relieve symptoms in chronic inflammatory conditions than NSAIDs. This was already observed with other polyphenols like cur- cumin [11]. Interestingly, a subgroup analysis showed that RIE effect on VAS pain was significant only in overweight/obese participants. Our study fails to bring an explanation to that finding. Both populations were similar in terms of pain or physical activity level at baseline. The only difference was the sex ratio. There were proportionally more men in the overweight/ obese group. One hypothesis would be that men are better responders than women to RIE treatment. This needs to be confirmed as we have not observed a dif- ference in RIE efficacy between men and women in the overall population. Another possible explanation would be that RIE through its anti-inflammatory prop- erties acts on systemic inflammation which is associ- ated with obesity. Inflammatory biomarkers should be explored to verify this hypothesis. Globally, this study also showed that 400 mg per day of RIE is the adequate posology to relieve VAS pain. It is at this dose that we recorded the most responders according to the OMERACT-OARSI criterion. We can also conclude that three months of treatment are nec- essary to obtain significant analgesia. This study showed promising effects of RIE on symp- toms of knee OA but should also be interpreted with caution because our study suffers from some limita- tions. First, RIE was not efficient on the primary out- come. The second main limitation was the small sample size as larger groups will be required to confirm the positive findings observed in this study [12].
Acknowledgements Not applicable.
Authors’ contributions YH participated in the analysis and interpretation of data, drafted and participated in the finalization of the manuscript. RLC conceived the study design, interpreted the results, participated in manuscript drafting, and was responsible for the final approval of the manuscript version to be submitted. PFB took part in the conception and design of the study, participated in the interpretation of data and final approval of the submitted version. RT per‑ formed the statistical analysis and reviewed the final version of the paper. MCS participated in the analysis and interpretation of data, drafted and revised the manuscript. GDG drafted the protocol, organized the study, and reviewed the final version of the paper. JMG performed the statistical analysis and reviewed the final version of the paper. AD drafted the protocol, organized the study, and reviewed the final version of the paper. The author(s) read and approved the final manuscript. Funding All the operational phase of this study (patient recruitment, data collection, and statistical analysis) was funded by Naturex and run by Atlantia. Availability of data and materials All data are available and can be obtained by sending a request by mail to Naturex SA, Avignon, France, or by e-mail to romain.le_cozannet@givaudan. com.
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Declarations
fruit peel extract reduces pain and stiffness and improves physical func‑ tion in adult patients with knee osteoarthritis. Nutr Res. 2010;30(9):601–6. 10. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162(1):46–54. 11. Henrotin Y, Malaise M, Wittoek R, de Vlam K, Brasseur JP, Luyten FP, Jiangang Q, Van den Berghe M, Uhoda R, Bentin J, De Vroey T, Erpicum L, Donneau AF, Dierckxsens Y. Bio-optimized Curcuma longa extract is effi‑ cient on knee osteoarthritis pain: a double-blind multicenter randomized placebo-controlled three-arm study. Arthritis Res Ther. 2019;21(1):179–90. 12. Ludwig IA, Mena P, Calani L, Borges G, Pereira-Caro G, Bresciani L, Del Rio D, Lean ME, Crozier A. New insights into the bioavailability of red raspberry anthocyanins and ellagitannins. Free Radic Biol Med. 2015;89:758–69. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations.
Ethics approval and consent to participate The study protocol was approved by the Central Ethics Committee of The University College Cork, Irland (namely Clinical Research Ethics Committee), agreement number: ECM 4 (I) 07/02/17. The study participants signed written informed consents before participation in the study. Consent for publication An informed consent to published results has been obtained from all participants. Competing interests YH received consulting fees from Naturex and is the founder and president of Artialis SA. RT from Atlanstats and JMG supported statistical analysis. RLC and PB are employees of Naturex. GDG and AD are employees of Atlantia. MCS has no disclosed conflicts of interest. Author details 1 musculoSKeletal Innovative Research Lab (mSKIL), The Center for Interdis‑ ciplinary Research On Medicines (CIRM), Department of Motricity Center, Institute of Pathology, University of Liège, CHU Sart-Tilman, level 5, 4000 Liège, Belgium. 2 Department of Physical Therapy and Rehabilitation, Princess Paola Hospital, Vivalia, Marche‑en‑Famenne, Belgium. 3 Artialis SA, GIGA Tower, CHU Sart-Tilman, Avenue de l’hôpital, 4000 Liège, Belgium. 4 Naturex SA, Avignon, France. 5 Atlanstat SA, Les Espaces Océane, 3, rue Jules Verne, 44400 Rezé, France. 6 BIOSCAR Inserm U1132 and Department of Rheumatology, Université de Paris, Hôpital 10 Lariboisière, 75010 Paris, France. 7 Atlantia Clinical Trials, Heron House Offices, Blackpool T23 R50R, Cork, Ireland. 8 Department of Statis‑ tics, Rouen University, Rouen, France.
Received: 23 February 2022 Accepted: 30 June 2022
References 1. FDA. Administration. Osteoarthritis: structural endpoints for the develop‑ ment of drugs, devices, and biological products for treatment guidance for industry- Services USDoHaH. 2018. 2. Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, Kraus VB, Lohmander LS, Abbott JH, Bhandari M, Blanco FJ, Espinosa R, Haugen IK, Lin J, Mandl LA, Moilanen E, Nakamura N, Snyder-Mackler L, Trojian T, Underwood M, McAlindon TE. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578–89. 3. Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis. Br J Sports Med. 2018;52(3):167–75. 4. Bourmaud M, Zarka M, Le Cozannet R, Fança-Berthon P, Hay E, Cohen- Solal M. Effect of Rubus idaeus Extracts in Murine Chondrocytes and Explants. Biomolecules. 2021;11(2):245. https://doi.org/10.3390/biom1 1020245. 5. Kim HR, Jeong DH, Kim S, Lee SW, Sin HS, Yu KY, Jeong SI, Kim SY. Fermen‑ tation of Blackberry with L. plantarum JBMI F5 Enhance the Protection Effect on UVB-Mediated Photoaging in Human Foreskin Fibroblast and Hairless Mice through Regulation of MAPK/NF-κB Signaling. Nutrients. 2019;11(10):PII:E2429. 6. Jean-Gilles D, Li L, Ma H, Yuan T, Chichester CO 3rd, Seeram NP. Anti-inflammatory effects of polyphenolic-enriched red raspberry extract in an antigen-induced arthritis rat model. J Agric Food Chem. 2012;60(23):5755–62. 7. Lecozannet R, Fanca-Berthon P, Falcao L, Tenon M, Bily A, Roller M, Feuillere N, Birtic, Simona. US2020222486A1. 8. Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, Togni S, Appendino G. Efficacy and safety of Meriva ® , a curcumin-phosphati‑ dylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev. 2010;15(4):337–44. 9. Farid R, Rezaieyazdi Z, Mirfeizi Z, Hatef MR, Mirheidari M, Mansouri H, Esmaelli H, Bentley G, Lu Y, Foo Y, Watson RR. Oral intake of purple passion
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