Trial Halted After 11 Infants Die in the Netherlands

Marcia Frellick

July 25, 2018

A Dutch trial involving treatment of pregnant women with the erectile dysfunction drug sildenafil has been abruptly stopped after 11 infants born to women who received the medication died, according to one of the trial sites, Amsterdam University Medical Centre (Amsterdam UMC).

The STRIDER (Sildenafil Therapy in Dismal Prognosis Early-Onset Fetal Growth Restriction) trial, which included 11 hospitals across the Netherlands and in other countries, started in 2015 and was to have finished in 2020. It was designed to determine whether sildenafil could increase fetal growth by increasing blood flow to the placenta in women whose fetus was severely underdeveloped.

Marc van den Broek, a spokesman for Amsterdam UMC, shared a statement with Medscape Medical News that said, "Previous studies have shown that sildenafil would have a positive effect on the growth of babies."

The statement described the early results of the Dutch trial: "At the moment of termination of the study, the results were known of 183 women, of whom just over half had taken the drug."

Of the 93 women in the sildenafil group, the statement said, "19 babies died, 11 of whom were due to a possible lung disease, a form of high blood pressure in the lungs; 6 babies also had this lung disease, but did not die."

In comparison, of the 90 women in the placebo group, "9 babies died. No one by the lung disease; 3 babies did have the lung disease, but did not die of it."

Sildenafil is approved to treat erectile dysfunction and pulmonary arterial hypertension and works by relaxing blood vessels. Although sildenafil is well known by the brand name Viagra, Pfizer, the maker of Viagra, was not involved in the trial, and another company's generic version of sildenafil was used, according to a Pfizer spokesperson.

Previous Studies Showed Different Results

The Amsterdam UMC researchers said the prognosis for the fetuses in the study was poor. "There is no known therapy to date to help these babies grow. Sildenafil...may improve the function of the placenta, as was shown in previous research. This can stimulate the growth of the unborn child."

According to the statement, "An interim analysis by Amsterdam UMC showed that sildenafil may be detrimental to the baby after birth. The chance of a disease of the blood vessels of the lungs appears to be greater and the chance of death after birth seems to have increased."

The researchers said they found no benefit of the drug for the children or the mothers. They said all adverse effects occurred after birth.

Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, United Kingdom, told Reuters that very few trials of sildenafil have been conducted in pregnant women and that there was no previous indication of the adverse effects seen in the Dutch trial.

"There have been other studies in this area, both involving preliminary work using animals and using pregnant women, and there was no indication that the treatment was dangerous based on previous research," he said.

Amsterdam UMC said the researchers "realize that this outcome has a huge impact on the women and her partner who participated in the study," adding that each of the participants had been notified personally.

Similar Trial Also Halted in Canada

The Dutch researchers said they expect the use of sildenafil for this application will stop worldwide.

Kenneth Lim, MD, with the University of British Columbia in Vancouver, Canada, who is principal investigator of a Canadian arm of the sildenafil trial, told Medscape Medical News in a statement, "The news out of the Netherlands is of deep concern to me, my research team, and all of the many international research partners involved in the study. The loss of a child under any circumstance is a tragedy for the parents and their loved ones, and we were very saddened and concerned upon learning of this news late last week."

Lim said investigators suspended the Canadian trial on the recommendation of members of the monitoring board. They will analyze data already gathered but said they were not aware of an increase in adverse outcomes among the 21 Canadian trial participants.

"We are working cooperatively with our international research partners in the Netherlands, the United Kingdom, Australia, and New Zealand to better understand the cause of the results in the Netherlands, and how they relate to results being reported by UK and other researchers, which did not indicate any evidence of harm," Lim said.

The BMJ reported today that the UK arm of the study, led by a team from the University of Liverpool, reported in February that sildenafil was ineffective at prolonging pregnancy or improving outcomes. Their results did not show any increase in adverse side effects except for a deterioration of blood flow in fetuses whose mothers were taking sildenafil.

The article said the lead investigator on the UK team, Zarko Alfirevic, MD, called that finding "potentially worrying" but reported that it might have been a chance finding. "They recommended extreme caution in any future studies that use a dose higher than 75 mg of sildenafil a day," the BMJ said.

The Dutch arm of the trial used the same dose as the UK arm — 75 mg daily, taken as three 25-mg doses — the BMJ said.

The BMJ article said, "An external inquiry into the failure of the trial is likely, but there is no evidence to suggest that it was poorly conducted."

Alfirevic told the BBC, "We need to be careful at this point to find out more. It needs a thorough investigation because the complications were not seen in the two other, similar trials that have already been done in the UK and Australia and New Zealand."

The lead investigator of the Dutch trial, Wessel Ganzevoort, MD, MPH, told Medscape Medical News the team plans to publish the early results of the Netherlands trial in a medical journal.

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