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.