Valoraciones sobre el trabajo en el discurso de las entrevistadas

The endometrial biopsy and use of Sitagliptin in healthy volunteers had been considered as safe and ethical for the purpose of this study.

I needed to explore other variables to ensure the utmost safety for participants and homogeneity of the study. These considerations formed the eligibility criteria for the study.

Factors which would determine the eligibility criteria involved 1. Menstrual cycle length and duration of treatment

We decided that participants would need to have a regular 28-30-day cycle for inclusion to the study. With a regular 30-day cycle there would be three menstruations and therefore three opportunities for stem cell recruitment to occur within the treatment period for each participant. Participants with longer cycles would not have the same number of opportunities for stem cell recruitment in the treatment period. Participants with a cycle length that is consistent would be more homogenous and therefore would minimise confounding factors.

2. Safety of Sitagliptin in healthy non diabetic individuals

The SPC for Sitagliptin was initially reviewed by myself, the pharmacy advisor and the hospital (UHCW) research governance manager. A plan was made with the trial sponsor (UHCW) for a formal review of the SPC every three months for the duration of the study. This would ensure the most up to date reference safety information was used and consistent with the protocol and participant specific documents. I also set up an email address

specifically for the trial called [email protected] and received any MHRA drug alerts to trigger extra reviews and updates.

We carefully studied the SPC for Sitagliptin to ensure our inclusion and exclusion criteria would only include participants in whom using Sitagliptin would be safe.

3. Concomitant Medications

Plasma monitoring of Digoxin would be required if taking it along with Sitagliptin. Sitagliptin appears to alter the hypotensive effects of enalapril. For this reason, those patients on digoxin or enalapril were not eligible for the study.

4. Renal Function

The SPC for Sitagliptin states that an assessment of renal function is recommended prior to its initiation because dose adjustment is required if there is mild, moderate or severe renal impairment. In order to accurately assess the true effect of Sitagliptin on the endometrium we needed all participants to be on the same dose. Therefore, we decided that all

5. Hepatic function

The SPC states that care should be exercised in the use of Sitagliptin in those with severe hepatic impairment. Only patients with normal hepatic function were therefore entered to the study.

6. Diabetes

Sitagliptin should not be used in patients with type one diabetes and dual therapy of Sitagliptin and other anti-diabetic medication is known to be associated with an increased risk of side effects such as hypoglycaemia which would require increased monitoring. Therefore, patients with type 1one or type two diabetes were not included in the trial.

7. Age

The safety of Sitagliptin has not been studied in patients under the age of 18. This was therefore the lower age limit for inclusion to the study. As the risk of miscarriage naturally sharply increases after the age of 42 this was the upper limit of inclusion to the study.

8. Body mass index (BMI)

There is no dose adjustment of Sitagliptin required for BMI. BMI has no clinically meaningful effect on the pharmacokinetics of Sitagliptin. Therefore, we did not need to limit inclusion to the study according to BMI.

9. Breast feeding

Caution is advised when prescribing Sitagliptin to breastfeeding mothers as it is not known if it is secreted in breast milk. Breast feeding patients would not be eligible for the study.

10. Safety of Sitagliptin in pregnancy

We needed to assess the safety of Sitagliptin in pregnancy in case pregnancy did occur during the treatment period. We contacted MSD and obtained reference safety information. This was studied carefully and has been considered in section 2.4 (Ethical Considerations).

There is too little data in the MSD company register to make a conclusion on the potential risk for humans and so Sitagliptin should not be used during pregnancy.

11. Avoiding pregnancy

Not only is Sitagliptin not recommended in pregnancy but the start and end of this study was marked with an endometrial biopsy. This obviously could not be performed if the participant was pregnant.

We decided that we will inform participants at the time of consent, that they must not try for a pregnancy in the cycle leading up to the first biopsy or for the duration of the study. The consent form required participants to be willing not try for a pregnancy and also to use barrier methods of contraception in the cycle leading up to the biopsy and for the whole duration of the study. Barrier contraception (condoms) were provided to participants at the time of consent.

If the couple had unprotected intercourse in the cycle leading up to the endometrial biopsy the procedure was cancelled.

After a trial management group (TMG) meeting with the sponsor (UHCW) it was decided that there needs to be clear pathways of checking for pregnancy through the study. This is detailed in the trial protocol.