Viagra trials to help low-growing fetuses are stopped after infant deaths | Science

By Jop de Vrieze Jul. When gynecologist Wessel Ganzevoort received an urgent meeting request from the independent committee to oversee his clinical trial last week, he thought this could be good news.

Ganzevoort is conducting a study to find out if sildenafil, sold under the brand name Viagra, could help low-growing fetuses if they are given to their pregnant mothers; the drug dilates the blood vessels and, in theory, could bring more oxygen and nutrients to the fetuses. A data and security monitoring committee, however, had reviewed the non-blind evidence in the midst of the study and wanted to talk. Ganzevoort, who is at the Medical Center of the University of Amsterdam (AUMC), knew that this probably meant two things: Either the drug worked so well that continue to give a placebo to half of the mothers in the trial would be unethical, or the study be stopped because sildenafil was causing serious complications. Because previous studies had shown no major side effects, Ganzevoort was waiting for that first.

He was wrong. At the meeting on July 19, the committee told him that a very specific complication, persistent pulmonary hypertension – in which the blood vessels of the baby's lungs did not open after birth – were unclear. was produced 17 times in the sildenafil-treated group, resulting in 11 deaths. There were only three cases of the condition in the placebo group and no deaths. (In total, there were 19 deaths in the treated group versus nine in the placebo group – the latter not being a surprise since all fetuses were at high risk because of their poor growth.) It took very little time for us to decide to stop the study, "says Ganzevoort. That same day, he and his colleagues began calling women who participated in the study, including several pregnant women or whose babies are in the hospital.

Researchers at the University of British Columbia in Vancouver, Canada, stopped a similar study, pending a thorough investigation of what happened in the Netherlands. But this sudden interruption probably meant the end of the road for what many thought was a promising therapeutic approach, says AUMAC gynecologist Ben Willem Mol, who co-initiated the study.

"Fetal growth restriction" is caused by a lack of blood flow from the placenta to the unborn child, resulting in undernutrition and stunted growth and development. It can lead to stillbirth or neonatal death, and surviving babies are even more at risk for infections and often suffer from long-term problems such as obesity and cardiovascular disease. Growth restriction is diagnosed with the aid of ultrasound, but now the only medical treatment closely monitors pregnancy and induces birth when the risk of stillbirth is considered high. This poses a difficult dilemma for doctors: inducing a birth prematurely increases the risk of complications, but waiting too long can lead to developmental abnormalities or stillbirth

The increase in placental blood flow could promote growth fetal. Worldwide, sildenafil is prescribed to pregnant women whose fetuses suffer from reduced growth. Viagra is known to dilate certain blood vessels, including those in the penis – which has become a star drug for erectile dysfunction – and a number of animal studies and small human trials have suggested that the drug might benefit the unborn children. Yet, no regulatory body has approved it for such use in pregnant women, so doctors have used it in an unnoticed manner on the label.

Ganzevoort and several other obstetric experts wanted to strengthen the evidence. On the question. In 2012, they launched an initiative to conduct five separate but very similar trials that would result in a meta-analysis.

The studies started in 2015, and even before the dramatic decision last week, the results were disappointing. A study by a team in the United Kingdom, published in The Lancet Child & Adolescent Health in December 2017, revealed that sildenafil did not improve the duration of pregnancy, the weight at the birth and fetal and neonatal survival. The team observed no adverse effects of the drug, except for a decreased blood flow from the placenta to the fetus by a shunt between the placenta and the fetus called ductus venosus. "It was an unexpected result and it was the first evidence of a potential negative effect of the treatment," says Gordon Smith of the University of Cambridge in the United Kingdom, who does not have the same effect. did not participate in the study.

The New Zealand team, whose results from a similar trial were presented at a recent meeting, did not find any profit either, but did not find any benefit. Nor has there been any complications, says Katie Groom of the Auckland University in New Zealand. A trial in Ireland has not started registration yet; The researchers in this study have not responded to e-mails today, but Mol expects it to be canceled.

The Dutch team hoped for a more positive result, until last week's call. "There was no sign of any serious damage, so we continued with our plan," says Ganzevoort.

The news was devastating to some of the study participants. "We were at peace with the death of our daughter, but now we are not," said a mother on Dutch public television. He also raised questions about the information received by parents about the risks of the study. The informed consent form they had to sign does not mention any potential negative effects for the child. "We have stated that sildenafil is not normally prescribed during pregnancy, and that no strange thing has been observed in this indication, which is a fact," says Ganzevoort, "but we could have specified more precisely that we do not know what we do not know, as I did during all the counseling that I did myself. "

How the drug could have caused the complications is not clear. The Dutch team plans to investigate all cases of pulmonary hypertension and neonatal deaths that it has caused to check if the diagnosis was correct and if there were any complications. 39; other specific characteristics among this group. One possible explanation is a "rebound effect," says Groom. Some of the drug has probably reached the fetus before birth, where she may have put dilation forces on the pulmonary vessels, she says; this could have led to an increase in the fetus's own constricting signals to prevent them from opening prematurely. "After birth, the child has stopped receiving the dilating drug, which can cause constriction of the pulmonary vessels," speculates Groom.

It is also not known why the deaths occurred only in the Dutch trial. The inclusion criteria of the study in the UK, Australia, New Zealand and the Netherlands differed slightly, but not enough to explain the varying results, says Groom. Researchers in the other two trials plan to check if they have missed cases of pulmonary hypertension in newborns.

Given the small number of deaths, it is also possible that the result in the Netherlands is entirely due to chance, even if Ganzevoort says the chances of this are less than 5%. "Combining our results with those of the other tests and zooming in on subgroups could give more clarity," he says.

The decision to stop the trial is a blow to the field, says Mol. "There was good reason to believe that this drug would work and he was responsible for conducting this test," he says. "I am moved to talk about it because we now have 11 families in mourning and that does not help these people."

There is always a risk in clinical trials, says Indira van der Zande, who has recently completed his PhD. . thesis on pregnant women in clinical research at the University Medical Center of Utrecht in the Netherlands. "But we should always keep in mind that by not doing this study there would also have been a risk, and doctors may have been prescribing this drug for years off label. assuming it is safe and effective. "