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Cardiac safety of nolasiban confirmed in Phase I clinical trial

5th May 2021

Richmond Research Institute, is a not-for-profit clinical research institute in London, UK, specialising in the safety assessment of existing medicinal products, exploring the usefulness of potential new medicines and providing scientific insights to improve clinical trial methodologies and strategies for personalised medicines. Here we report our recent work on the cardiac safety of nolasiban.

Why was this research needed?

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the chance of successful pregnancy and childbirth among women undergoing embryo transfer following assisted reproductive technology, such as in-vitro fertilisation.  

However, as oxytocin receptors are present in the heart, the direct cardiac effects of nolasiban should be determined by measuring the electrical activity of the heart and any changes in the time it takes the ventricles to contract and relax, known as a thorough QT study.  Determining the cardiac safety of  drugs is an important part of drug development, cardiac toxicity is among the reasons many drugs fail during the development process.

What was the aim of the clinical trial?

Cardiac toxicity can cause changes in a person’s heart rhythm, called arrhythmias, or even prevent the heart from pumping enough blood around the body.  The cardiac safety of a single dose of nolasiban (900 mg or 1800 mg) was compared with a placebo1.  

How was the trial done?

Forty-five healthy women between 20 and 37 years of age underwent robust cardiac assessments before, during, and after treatment at our state-of-the-art clinical research facility at Richmond Pharmacology, London.  

  • 14 women received a single 900 mg nolasiban  
  • 16 women received a single 1800 mg nolasiban
  • 15 women received a single placebo

Electrocardiograms (ECGs) were performed to test for the presence of arrhythmias.  These record the rhythm, rate, and electrical activity of the heart.  These recordings were then extensively analysed before, during, and after treatment using QT/QTc intervals which detected any changes (Figure 1).

Figure 1 shows an electrocardiogram trace with the QT interval marked out. The QT interval is the time it takes for the large chambers of the heart, known as the ventricles, to contract and then relax ready to contract again per heartbeat.  QTc means the QT interval corrected for heart rate.

Figure 1 – QT interval

The ability of the trial, or sensitivity of the assay, to consistently detect changes in QTc was assessed by measuring the effect of ingesting a balanced lunch 4.5 hours after nolasiban or placebo administration.

What were the results?

During cardiac assessments, a shortening of 5 milliseconds (ms) on QTc was seen immediately after nolasiban or placebo administration compared with before-treatment readings.  

There were no significant changes seen in QRS duration, QRS axis, QT interval or RR interval during the trial.  A marginal heart rate increase of up to 4.3 beats per minute was observed, but this finding was neither statistically nor clinically significant.  

Detailed analyses of the changes in QTc after food administration showed a shortening of between 7.5 and 11 ms. Furthermore, the 90% confidence intervals2 were well below 5 ms.

These results confirm that the experiment is sensitive enough to detect small changes in QTc.

How has this research helped patients and researchers?

Nolasiban treatment at a dose of 900 mg or 1800 mg did not lengthen the QTc interval, providing reliable data on the absence of cardiac toxicity in healthy females of childbearing age and supporting evidence of the previously reported cardiovascular safety findings.  

Furthermore, Richmond Research Institute has previously demonstrated the value of adding a food arm in early phase QT/QTc studies.  Our findings in this trial provided further evidence that the shortening in QTc in response to a standardised meal can be a useful and reproducible means to confirm the sensitivity of an assay and a valuable method for studying groups at risk of QT-prolongation.

Read the full results in the paper published in Nature.

1 A placebo does not contain any active ingredient(s) and has no therapeutic value.  Placebo treatments help researchers prove whether a new treatment is safe and effective.

2 A 90% confidence interval is a statistical estimate.  In this trial, the confidence interval provides a range of values that you can be 90% certain contains the true average change in QTc.  The confidence intervals in this trial were narrow, meaning the likelihood of variation in the QTc value is low, thus confirming the sensitivity of the assay in detecting small changes in QTcA 90% confidence interval is a statistical estimate.  In this trial, the confidence interval provides a range of values that you can be 90% certain contains the true average change in QTc.  The confidence intervals in this trial were narrow, meaning the likelihood of variation in the QTc value is low, thus confirming the sensitivity of the assay in detecting small changes in QTc.

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