Results
A total of 1493 women were screened for eligibility from 9 July 2015 through 30 April 2019, and 164 of these women were randomly assigned to receive either folic acid 5mg tablets (n =83) or placebo (n =81). Since women were allowed self-referral, and given the strict inclusion and exclusion criteria, a high number of screened women (89%) were deemed ineligible for randomisation. For 105 (67%) randomised women, full compliance to the 12 weeks of allocated treatment was recorded, with only 13 (8%) women receiving no treatment and compliance was balanced across treatment arms (Figure 1). The percentage of women with available data for the primary outcome was 87% (143; 74 in folic acid and 69 in placebo). The characteristics of the participants at baseline were similar in the two groups as demonstrated in Table 1. The compliance data was collected at weeks 4, 8, and 12 and presented in Table 2.
Primary outcome: The mean Composite Hot Flush Score B decreased over time in both groups and the mean change at week 12 was -6.98 (10.30) and -4.57 (9.46) for folic acid and placebo group, respectively. The difference in the mean change between groups was -2.41 (95% CI: -5.68, 0.87) with t-test givingp =0.149. From the adjusted linear regression model, the difference in the mean change was -2.61 (95% CI: -5.72, 0.49) withp =0.098. There was no statistically significant difference between the two groups at other time points (Figure 2 and Table S1).
Secondary Outcomes: There was no statistically significant difference for severity score B, frequency score B or the number of responders at any time point (Figure S1, Table S1). A lower score for Greene Climacteric Scale represents an improvement in symptoms. The scores were similar for both groups and no statistically significant difference was found at any time point for any subscale score. A higher score equates to better QoL for Utian QoL Score. The scores were similar for both groups and no statistically significant difference was found at any time point for any subscale score except for the total score and emotional score at week 8. The mean changes from baseline in total score and emotional score were statistically significantly higher for folic acid group when compared to placebo. The number of women with data available for the total score and emotional score at trial entry and week 8 was 151; 77 for folic acid group and 74 for placebo group. The mean change (SD) from baseline in total score was 0.88 (12.54) and -4.34 (12.69) for folic acid group and placebo group, respectively. The difference in the mean change was 5.22 (95% CI: 1.16, 9.28). The mean change (SD) for emotional score from baseline was 1.34 (5.11) and -0.54 (5.12) for the folic acid group and placebo group, respectively. The difference in the mean change was 1.88 (95% CI: 0.23, 3.52). The overall climacteric symptoms and QoL analysis are presented in Figure 2. The detailed analysis for all domains at various time points are presented in Figures S2 and S3 and Table S2. None of the primary or secondary outcomes provided a statistically significant result when analysed using Multilevel mixed-effects modelling (Table S3 and S4).
The mean change (±SD) in serum folate at week 12 was significantly higher in the folic acid group (11.06 ± 3.86) when compared with placebo group (0.66 ± 3.15), and the difference in the mean change was 10.39 (95% CI: 9.18, 11.61) with p <0.001 (Table S5).
Since there was no data for the primary outcome analysis for 21 women, a sensitivity analysis was performed. It was possible to impute data for a further 15 women thus increasing the total number to 158. The mean change (SD) in Hot Flush Score at week 12 was -6.79 (10.21) and -4.09 (9.82) for folic acid and placebo group, respectively. The difference in the unadjusted mean change was -2.69 (95% CI: -5.88, 0.50) with p =0.099. The difference in the adjusted mean change was -2.82 (95% CI: -5.87, 0.24) with p =0.071. The sensitivity analysis was repeated using the LOCF procedure which displayed similar results (Table S6).
The frequency of adverse events was similar in the two treatment groups. In total, 43 adverse events were observed in 19 women; 22 were observed in 12 women on folic acid and 21 were observed in 8 women on placebo. All these were reported as grade 1 except one as grade 2 and five as grade 3. All events resolved spontaneously. The causality of the treatment with these adverse events is hard to ascertain but were considered unlikely to be related. The details of events and grades are provided in Table S7.