The SIMPLANT study opened for recruitment on the 15th September 2016. We had randomised 4 participants within the first month. On the 21st October 2016 the study was suspended by the sponsor due to a serious breach of the trial protocol. This breach was related to screening and eligibility criteria.
As described in the protocol, normal renal function was necessary for participants to be eligible for the study. This is because the SPC for Sitagliptin states that before initiating Sitagliptin at the standard dose of 100mg, normal renal function should be confirmed and for patients with an estimated glomerular filtration rate (eGFR) below 50mL/min the dose of Sitagliptin should be lowered. We needed all participants to be on the same dose to look at the true effect of Sitagliptin on the eMSC count. Therefore, normal renal function was part of the eligibility criteria so that a standard dose of 100mg of Sitagliptin could be safely administered.
The eligibility criteria on the original proposed protocol stated ‘normal renal and hepatic function’. When the initial application with this protocol was made to the REC, one of the recommendations was the need to define ‘normal renal and hepatic function’.
The protocol was amended and I had defined normal renal function with the reference ranges from the laboratory at UHCW (Urea 2.5 – 7.8mmol/L, Creatinine 50 -90umol/L, potassium 3.5 – 5.3mmol/L, Sodium 133 -146mmol/L). I had no reason to suspect that the young and healthy group of patients who would be approached for this study would not have normal renal function and hepatic function.
Some of the above components of a renal or liver function test can however be altered by hydration status. For example, a slightly low creatinine or urea level is of no clinical significance and actually only expresses normality for this population of young fit and healthy women. If a creatinine level is lower than the normal range or a bilirubin level is lower than the normal range, this result is actually viewed as better than normal. Clinically, these slight deviations from the specific laboratory reference ranges would not be viewed as abnormal.
Soon after the trial opened for recruitment we realised that the inclusion and exclusion criteria were too tight. This issue became apparent when a patient was deemed eligible to enter the study as her renal function was better than normal as she had a marginally lower urea level than the normal range. This was however unacceptable due to the reference ranges in the protocol. At this point I realised that clinical judgement had no bearing on defining eligibility of the patient. This only came to light when I called the randomisation team on the day of her first
intervention visit.
After her endometrial biopsy was performed the randomisation team revealed that they would not be happy to perform randomisation as the participant did not actually fulfil eligibility criteria. Long discussions between the chief investigator and the trial manager left us in a position only to be told to break the news to the participant that she had to be withdrawn from the study.
When explaining the situation to the participant she explained that she had 3 litres of water to drink just before her blood test was performed and questioned whether this was the reason her blood test was abnormal.
With this new information we concluded that her blood tests were actually clinically invalid and needed to be repeated. We repeated her renal function tests which were now within normal range. The randomisation team were called with the new set of results and she was successfully randomised. She started medication that day. Repeating the blood tests and effectively re-screening the participant to confirm eligibility was identified by the sponsor as a serious breach of the protocol. This lead to a local formal investigation straight away.
An investigation of all patients who had been screened for the study took place by the sponsor. There were other patients who had been deemed eligible as their renal and hepatic function were clinically normal. However, there were certain values within the tests which were marginally out of the reference range, in fact their results were better than average, however, were not within the range specified in the eligibility criteria and so the sponsor deemed this is as persistent non- compliance with the protocol and was therefore reported as a serious breach of protocol.
The trial was suspended on the 21st October 2016. The notification of this serious breach of the trial protocol was made to the REC and MHRA by the sponsor on the 24th October 2016.
The sponsors directed me to
1. Recall and remove the patient who had been screened twice prior to randomisation
2. Remove patients who had been consented based on their blood test results which did not actually meet eligibility criteria.
These were difficult phone calls to make. Fortunately, the patients were very understanding and appreciative of the care they had received so far. They were all asked if they would like to participate in any other RPL trials in the future which they were all happy for.
Between the 21st October 2016 and 15th December 2016 I worked hard with the chief investigator and sponsors to get the trial open again. We submitted 2 substantial amendments through the REC and MHRA.