Henrotin et al. BMC Musculoskeletal Disorders
(2022) 23:650
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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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