Nutrients 2023 , 15 , 2688
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analysis group, baseline value, time since menopause at screening, BMI at baseline, analysis subgroup, and interaction analysis group × analysis subgroup. For bone biomarkers, the changes from baseline in each parameter were analyzed at week 48 using a mixed model for repeated measures (MMRM), including the following covariates, in addition to analysis group and baseline value: time since menopause at screening and BMI at baseline. Comparisons within and between groups were studied. Regarding the other secondary and exploratory outcomes, depending on planned time points, an ANCOVA at week 48 including analysis group and baseline value or a MMRM including analysis group, visit, baseline values, and group*visit interaction was performed. For all analyses, normality distribution of the residuals was verified by Skewness and Kurtosis. If the adequacy of the model could not be validated, the parameter was derived using the log transformation of the values at each time point and was then modeled with the same model characteristics. If the adequacy of the new model was not able to be validated on the log transformation, a non-parametric analysis of covariance, based on ranks (rank ANCOVA) with the same covariates was performed for the comparison between groups and Wilcoxon signed-rank test for the comparison within group. Regarding safety, all analyses were performed on all participants who received at least one dose of study treatment according to the analysis groups. The incidence of AEs was assessed, and a description according to SOC and PT was tabulated. The number of patients with at least one TEAE was compared between analysis groups using a chi-squared test. Normal data were reported as means ± SD and non-normal data as median (Q1; Q3). All statistical tests were conducted two-sided with a significance level of 5%. No adjustment for multiplicity was considered.
3. Results 3.1. Baseline Characteristics of the Study Population
A total of 221 women were screened, among whom 100 were deemed eligible and assigned randomly to HE ( n = 50) or placebo ( n = 50) groups. Five participants were lost to follow up (three in the HE group and two in the placebo group), and ninety-five participants fully completed the 48-week trial. Three participants in the placebo group were excluded from the FAS because they had no post-baseline value for any of the efficacy criteria (Figure 1). Baseline data of the FAS population are presented in Table 1. Both groups were bal- anced on all the parameters presented. The participant mean age was 62.2 ± 6.3 y (range: 50; 77 y), and time since menopause was 12.6 ± 7.1 y (range: 1.1–31.8 y) with a slightly higher prevalence of women > 10 years post-menopause in the placebo group, 70% compared to 48% in the HE group (no statistical test performed). Mean BMI was 24.9 ± 3.1 (range: 18.6; − 31.9), with 54% of the participants within normal range and 46% in an overweight and obese range. Mean serum 25-OH D3 concentration was 79.2 ± 27.7 nmol/L (range: 21; 155). The vitamin D status was considered sufficient if serum 25-OH D3 ≥ 75 nmol/L versus in- sufficient if <75 nmol/L [40]. A slightly lower prevalence of vitamin D insufficient women was observed in the HE group, 42% compared to 52% in the placebo group (no statistical test performed). All participants had osteopenia with an average T-score at the lowest siteof − 1.64 ± 0.41g/cm 2 (range: − 2.4; − 1.0). Two participants ( n =1HE; n = 1 placebo) were enrolled despite that they met the exclusion criteria regarding significant endocrine disorder as they had diabetes. Their data were included in the statistical analysis as they are part of the FAS. 3.2. Safety and Compliance to the Intervention Participant compliance to the IP was good with only 17% and 13% of participants who were non-compliant in the HE and placebo groups respectively. Similarly, compliance of the CaD supplements was good with only 11% and 4% of participants consuming <80% or >120% of the supplements in the HE and placebo group, respectively. Both HE and placebo capsules were well tolerated.
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