Secondary Analysis (Adjusted Analysis)

Table 9.0.3 gives an estimate of the difference in mean eMSC at baseline between the two groups (Row 1) and an estimate of the difference in the mean eMSC at the final biopsy between the two groups (Row 2). It also gives an estimate of the difference in the mean eMSC between the final biopsy and the baseline biopsy in each treatment group separately (Row 3 and Row 4).

TABLE 9.0.3: Adjusted Analysis of eMSC Counts Between Baseline and Final Biopsy and Between Both Treatment Groups

Row

Effect

Difference

Estimate (95%

CI)

P-value

1

Month 1 (Baseline biopsy)

Group 1- Group 0

-0.72 (-1.52, 0.0870)

0.071

2

Month 3 (Final biopsy)

Group 1 – Group 0

-0.17 (-0.9709,

0.6239)

0.660

Group 0

Month 3 – Month 1

0.06(-0.0775,

0.2051)

0.3750

Group 1

Month 3 – Month 1

0.61 (0.4375, 0.7761)

<0.001

Row 1 gives an estimate of the difference in the mean eMSC count between groups 0 and 1 at baseline. The difference is -0.72 (Group 1 – Group 0) (95% CI -1.52, 0.09), which is almost one extra colony of stem cells in group 0 at baseline than group 1. Participants in Group 0 were also on average older than Group 1. Although the difference is not statistically significant the p-value is small (p=0.071) and the confidence interval varies from -1.52 to 0.08 suggesting a tread towards a difference. These results reflect the profiles in figure 9.0.9 where the groups did not seem well balanced at the baseline biopsy.

9.8.1 PRIMARY OUTCOME MEASURE

Row 2 gives an estimate of the difference in mean eMSC count between groups 0 and 1 at the final biopsy (month three). This is effectively our primary outcome measure; the stem cell count after three months.

The difference between the two groups is - 0.17 (Group 1 – Group 0) which is small and not statistically significant (p=0.660).

The results reflect the profiles in Figure 9.0.9, where the eMSC count at 3 months for the two groups overall seemed similar.

The unadjusted analysis revealed the mean difference in the eMSC count between the two groups at the final biopsy to be 0.0026 (p=0.971). The adjusted and unadjusted analyses were different as we adjusted for the difference in age and the baseline eMSC count between the two groups.

9.8.2 OTHER RESULTS

Although there was no significant difference in the eMSC count after three months between Group 0 and Group 1 there are some other interesting results.

We looked at the difference in the eMSC count between the initial and final biopsy between the two treatment groups.

Row 3 of Table 9.0.3 gives an estimate of the difference in the mean eMSC count between the baseline and final biopsy in group 0. The difference is 0.06 (month 3 – month 1) which is very small and not statistically significant (p=0.370).

These results again are reflected in the profiles in 9.0.10 where it can be seen that there were only very few participants in this group who appeared to have a large change in the eMSC count between the baseline and final biopsy.

Row 4 gives an estimate of the difference in the mean eMSC count between the final and baseline biopsy in group 1. The difference is 0.61 (month 3 – month 1) which is 10 times higher than the change in group 0. The difference in group 1 is highly statistically significant (p = <0.001) and the confidence interval is narrow. This significant result for participants in group 1 may indicate a therapeutic target. This difference of nearly one colony per 1500 cells is biological significant. This is

because each colony contains in the region of 100-1000 cells that have originated from one cell in just the 10 days of the assay. If this is viewed in the context of the whole endometrium with millions of cells, one extra stem cell colony with the ability to reproduce exponentially and rapidly per 1500 cells would translate to thousands of additional colonies each able to make thousands more cells. Hence one extra stem cell-forming colony per 1500 cells could make a large biological difference to endometrial regeneration.

Figure 9.0.10: Graphical Representation Of Adjusted Secondary Analysis (Expected profiles for women of 33 years (median age in the whole cohort) in

groups 0 and 1)

The graph in figure 9.0.10 represents the information in the table of results from the adjusted secondary analysis.

The final eMSC count in group 0 and group 1 was not significantly different. The null hypothesis is therefore correct.

eM S C co un t Biopsy 1 Biopsy 2 0 0. 25 0. 5 0. 75 1 1. 25 1. 5 1. 75 2 2. 25 2. 5 2. 75 3

Expected counts for woman of 33 years in group 0 Expected counts for woman of 33 years in group 1

Other observations were that there is a higher baseline mean count in group 0 than group 1, Group 0 did not have a statistically significant increase in the eMSC count between the baseline and the final biopsy and Group 1 had a statistically significant increase in the eMSC count between the baseline and final biopsy.

9.9 SECONDARY OUTCOME MEASURES

9.9.1 ADVERSE EVENTS AND SIDE EFFECTS

Table 9.0.4: Adverse Effects and Side Effects in Each Treatment Group

Adverse event/Side Effect Group 0 n= 15 Events (participants, %)

Group 1 n = 15 Events (participants,%) Headache 26 events (7 participants, 47%) 7 ( 3 participants, 20%)

Dizziness 0 1 Nausea 0 0 Thirst 0 1 Myalgia 1 1 Diarrhoea 2 (2 participants) 0 Dry mouth 1 1 Rash 2 (1 participant) 0 Chills 1 1 Night sweats 0 1

Mouth ulcers 2 (1 participant) 0

Nose bleed 1 0

UTI 0 1

Reported adverse reactions related to Sitagliptin which occur in >5% of patients include symptoms of an upper respiratory tract infection, nasopharyngitis and headache. In our study there were 7 participants (47%) who suffered with at least one headache in the three-month period in Group 0 and 3 participants (20%) in Group 1 who suffered with at least one headache in the three-month period.

Using the Fisher’s Exact Test, the difference in participants experiencing headaches between the two groups is not significant (p = 0.245).

All other adverse events occurred in a maximum of one participant in one group. There was one participant who suffered with diarrhoea once and mouth ulcers on twice.