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Participants in this study would need to consent to having 2 endometrial biopsies and take oral trial medication every day for 3 months.

2.4.1 ENDOMETRIAL BIOPSY

Endometrial biopsies are taken with the Wallach endocell endometrial cell sampler, which is a simple and safe manual suction device routinely used to take endometrial biopsies in gynaecology clinics.

Endometrial biopsies take approximately three minutes to perform in an outpatient setting however, they are intrusive and cause discomfort. Hence, all women would be given verbal and written information regarding the biopsy procedure to ensure they were adequately informed of this prior to seeking their consent for this study and the biopsy.

In mitigations of discomfort of the procedure it is possible that the biopsy itself is beneficial to future pregnancy outcome. Along with the injury of menstruation it has been demonstrated in chapter one that performing an endometrial biopsy initiates a wound healing response which may enhance stem cell recruitment to the

endometrium.

2.4.2 TRIAL MEDICATION SAFETY AND SIDE EFFECTS

Participants in this study would also need to consent to taking study medication every day. There was a 50% chance of this being Sitagliptin and a 50% chance of this being placebo. There are always ethical considerations to consider with the use of placebo but we also had to explore the safety of Sitagliptin for this non-diabetic patient cohort.

Sitagliptin is routinely used by patients with type 2 diabetes who often have multiple co-morbidities with a very low incidence of reported side effects. It is used as monotherapy or dual therapy in combination with insulin, metformin or sulphonylureas.

I studied the Summary of Product Characteristics (SPC) for Sitagliptin from the electronic Medicines Compendium (EMC) which contains up to date information about medicines licensed for use in the U.K. I was able to establish common and uncommon side effects, contraindications, interactions with other medication and pre-prescribing checks.

Sitagliptin was developed by Merck & Co (MSD). The lead pharmacist at UHCW for clinical trials requested information from MSD on the safety of Sitagliptin in healthy humans and also on the safety of Sitagliptin in pregnancy. These documents were reviewed thoroughly by myself, the pharmacy team and the Research and Development governance team at UHCW.

Sitagliptin has a high safety profile. The SPC states that the only common side effect (frequency ³ 10%) is a headache. All other known side effects occur less frequently. Side effects occurring in approximately 5% include upper respiratory tract infections and nasopharyngitis. Up to 5% have been known to suffer with osteoarthritis or pain in extremities.

Side effects for which the frequency is unknown includes hypersensitivity, interstitial lung disease, vomiting, acute pancreatitis, angioedema, rash, urticaria, exfoliative skin conditions, arthralgia, myalgia, and impaired renal function. These have mainly been reported as individual case reports.

Some adverse reactions are observed mainly in those using a combination of Sitagliptin and other diabetic medication together rather than with Sitagliptin monotherapy. These include hypoglycaemia, influenza, nausea and vomiting, constipation, peripheral oedema and dry mouth.

2.4.3 SAFETY OF SITAGLIPTIN IN HEALTHY NON-DIABETIC INDIVIDUALS

The various RCT’s looking into the safety of Sitagliptin in healthy patients showed that Sitagliptin monotherapy did not lead to hypoglycaemia (Devin et al., 2014; Herman et al., 2005; Mistry et al., 2008), ECG changes (Mistry et al., 2008) or altered immune function (Price et al., 2013).

There were reports of transient light headedness and nausea which both resolved after stopping the medication. Overall there were no adverse drug events and

Sitagliptin was well tolerated at 25/50/100/200/400 mg doses (Bergman et al., 2007).

The protocol for the study was peer reviewed by Dr O’Hare who is a consultant diabetologist. Dr O’Hare with clinical experience of using Sitagliptin confirmed that we would not need to monitor blood glucose levels of participants and confirmed safety of the medication in the healthy population.

2.4.4 SAFETY OF SITAGLIPTIN IN PREGNANCY

It was expected that participants entering this study would need to avoid pregnancy for the duration of the study to allow them to have two endometrial biopsies over 3 months and also allow time for this pre-conception treatment to take effect.

I did however have to consider the safety of Sitagliptin use in pregnancy in the event of pregnancy occurring in any of the participants while on study medication. There is lack of human data on Sitagliptin to currently recommend its safe use in pregnancy however there are post marketing reports of exposure during pregnancy on the Merck &Co pregnancy register.

Merck pregnancy registries have prospective and retrospective data collection systems aimed at detecting adverse effects of certain drug use in pregnancy. This register receives voluntary reports from women or healthcare providers for women who have taken Sitagliptin or Sitagliptin and metformin during pregnancy. The importance of reporting all outcomes of exposure to Sitagliptin in pregnancy as early as possible is emphasised. This facilitates the collection of prospective unbiased information. It is important to note that retrospective reports to the company pregnancy register will contain bias towards reporting mainly abnormal outcomes. The fifth annual cumulative review produced by Merck & Co for Sitagliptin/Sitagliptin +metformin contained post marketing pregnancy reports received from reports from August 2006 to August 2011. There was a total of 16 complete prospective reports which included 14 live births (one set of twins) and three spontaneous miscarriages. No congenital anomalies were reported in any of the exposed pregnancies (Merck & Co, 2015).

A pre and postnatal development study performed in rats showed no adverse effects with the use of Sitagliptin. Reproduction studies on rats and rabbits given

doses 12 times the maximum human dose did not impair fertility or harm the fetus (Co, 2017).

Most case reports on outcomes of fetuses exposed to Sitagliptin are from mothers with uncontrolled diabetes despite the use of metformin or insulin. It is difficult to ascertain if miscarriage is a result of embryonic abnormality, diabetic embryopathy or polytherapy.

The SPC for Sitagliptin states that ‘there is no adequate data from the use of Sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. Due to lack of human data, Sitagliptin should not be used during pregnancy’.

Overall, there is not enough data in the pregnancy register to allow an analysis of pregnancy outcomes by type or by timing of exposure. The SPC does not recommend the use of Sitagliptin in pregnancy and this needed to be taken into account for the purpose of the study.

Sitagliptin has been assigned FDA pregnancy category B (Co, 2017). This American pregnancy risk category classification (A, B, C, D or X) indicates the potential risk of a drug to be teratogenic or harmful if used in pregnancy. FDA category B indicates that animal studies have failed to show a risk to the fetus but there are no adequately well controlled studies in humans.

Although there are no adequate and well controlled studies in pregnant women there were no teratogenic effects when female rats were administered 20 – 30 times the maximum recommended human dose (25mg/kg in rats and 125mg/kg in rabbits). Doses approximately 100 times the maximum human dose increased the risk of rib malformations in offspring. Because of the high safety margins, these findings do not suggest a relative risk for human reproduction.

When Sitagliptin was administered to rats at a dose 100 times that of maximum human exposure from 6 weeks’ gestation to 21 days post-natal there was a reduction in body weight in offspring. No functional behavioural toxicity was observed in the offspring of the rats.

In order to reduce the risk to any fetus, a series of measures were put into place to minimise the risk of women conceiving on the study medication. We also included measures to ensure that if pregnancy did occur, it was detected early and the study

medication was discontinued as soon as possible. Details of the measures put in place by the trial management group are in the trial protocol.

2.4.5 INVESTIGATION MEDICINAL PRODUCT AND PLACEBO

Once it was deemed safe to give Sitagliptin to healthy non diabetic participants I started contacting companies who made placebo’s for the supply of Sitagliptin and placebo. We had quotes from three separate companies.

After close liaison with the trial pharmacist we felt that Sharp Clinical Services were best placed and best value for money to manufacture and supply the study requirements.

Sharp clinical services were responsible for the packaging, labelling and transport of the study medication to the research study site.

Sitagliptin is usually issued in a tablet form. To ensure the study was blinded, the Sitagliptin tablets were converted to capsule form to make them identical to the placebo.

Sitagliptin was encapsulated because it was substantially cheaper to produce placebo in capsule form rather than in tablet form. The encapsulated Sitagliptin then had to undergo disintegration testing to ensure it had the same bioavailability and shelf life as the original tablet form.