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 Nine participants withdrew prematurely from the study, five of these were withdrawn due to an adverse event/SAE, one participant was withdrawn due to receiving a clinically abnormal blood result, one participant was withdrawn due to a lack of study product, and two participants did not give reasons for their withdrawal. All other 198 participants completed the study as planned (Fig. 1).
203 participants were included in the Safety population as they took at least one dose of the product, 198 participants were considered eligible for the ITT analysis. Among the ITT population, 68 participants received a placebo, 66 RIE 200 mg, and 64 RIE 400 mg. The cumulative time distribution of withdrawals was similar in the three groups without significant differences in the reasons for withdrawals (Fig 1; Appendix 1). At baseline, participants in each group were well-matched (Table 1). Female and male were equally distributed between 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 diagnosis of OA. 53% had a Kellgren-Lawrence score of 1 and 38% had a Kellgren-Lawrence score of 2. The remaining participants (9%) had a Kellgren-Lawrence score of 3. No significant differences were observed between the three treatment groups according to demographic characteristics and BMI. Fifty-one participants had a BMI < 25 kg/m2 and 147 a BMI ≥ 25. At baseline, global WOMAC and subscores, VAS pain, SF-36, SPPB, and IPAQ scores were not significantly different between BMI groups (Appendix 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 difference between treatments. However, 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 reduction induced by RIE was over – 7 mm which was clinically relevant, and reached clinically statistical difference compared to placebo at the highest dose (-7.09 (2.71); 95% CI, -13.11 to -1.07; p=0,017) (Fig.2, Table 2).
After 12 weeks of treatment, subgroup analysis on the participants with a BMI ≥ 25, highlighted clinically relevant VAS pain reduction for the 200 and400 mg doses compared to baseline of respectively -11.25 (2.14) mm and -13.36 (2.26) mm (placebo = -0.37 (2,16) mm). The reduction 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 function 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 treatment (p = 0.042). In the normal BMI group, a higher decrease of 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) (Appendix 3).
RIE had no significant effect on the other secondary end-points (IPAQ, SF-36, walking distance in treadmill 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 fulfilled the OMERACT-OARSI criteria in RIE 400 mg group, but only 45% in placebo (p=0.04) (Fig. 4).
There were two not-related-to-product Serious Adverse Events (SAE) reported in this study. One participant had a severe SAE as they were diagnosed with prostate cancer. This participant was withdrawn from the trial due to SAE after visit 1. The other participant had a moderate SAE due to renal calculus. This participant recovered within three days and remained in the trial.
There were 123 AEs reported by 90 participants (44.3%) in total. The majority of AEs were unlikely or unrelated to RIE (N=99; 80.5%). In addition, 95.1% of AEs were mild to moderate intensity. There were 24 AEs possibly-related-to-product where 83.3% of these possibly related AEs occurred on the active product (N=11 for RIE 200mg; N=9 for RIE 400mg). Eight (33.3 %) of the possibly-related-to-product AEs were due to abnormal clinically significant blood results, twelve (50.0 %) were due to gastrointestinal issues, two (8.3%) were due to skin rashes and two (8.3 %) were due to swollen knees. There were only two severe adverse events (swollen knee for RIE 200mg and epigastric pain for RIE 400mg) which were possibly related to the product with the participant experiencing epigastric pain recovering by end of the study. 191 participants returned their product by end of the trial and the population had high study product compliance and adherence to protocol. For the participants 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 analysis 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 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 end of the study, 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 baseline and week 12. The active product group (either dose) attended to have a higher incidence (61.5%; N=24) of reducing their rescue medication use compared to placebo (38.5 %; N=15).