The vital clinical trials that are saving babies’ lives

Each year, one in 10 of the more than
300,000 babies born in Australia arrive prematurely. Premature babies, especially those born more than eight to 10 weeks
early, face challenges with nearly every major organ system. These
babies will be admitted to either a neonatal intensive care unit or a special
care nursery.

For parents of premature babies, the first
days after birth are frightening and disorienting; filled with flashing lights,
unintelligible medical jargon, and the trauma of seeing their newborn connected
to an array of machines and devices.

“What we’ve gone through, our experience,
you just can’t take that away,” says Melinda
Cruz, mother of three premature babies and co-founder of the Miracle Babies Foundation,
which provides support to families with premature and sick newborns.

It’s also during these fraught hours and
days that parents may be approached to enrol their baby in a clinical trial.

“Had we been approached at the time, we
probably would have said no,” says Cruz.

Now, 16 years after the birth of her first premature baby, Cruz is central to a partnership between parents and medical researchers. Their goal is to see parents become active colleagues in clinical trials, and for everyone to see trials as part of routine care.

Rethinking
the norm

Small variations in the routine treatments that premature babies receive soon after they are born may significantly influence their survival, explains Professor William Tarnow-Mordi, Director of Neonatal and Perinatal Trials at the National Health and Medical and Research Council (NHMRC)  Clinical Trials Centre.

“What happens in
the first 15 minutes from birth can dramatically alter the rest of a baby’s
life,” he says.

In
2010, the Australian Placental Transfusion Study (APTS), led by Tarnow-Mordi,
tested a simple idea: instead of clamping the umbilical cord of a very
premature baby immediately after birth, obstetricians were asked to wait at
least a minute before doing so.

The researchers
wanted to test whether babies given this extra time were more likely to survive
without complications, perhaps because it helped them receive more stem cells
and red and white blood cells from their mothers, leading to less anaemia and
infection and better tissue repair. Or perhaps it allowed them to start breathing
by themselves without invasive procedures.

Early indications
suggest that the benefits of delayed cord clamping were much greater than expected.
A combined analysis of the data from the APTS and 17 other randomised clinical
trials showed that delayed cord clamping reduced the risk of mortality in
babies by one-third. And it reduced the number of babies getting later blood
transfusions by 10%.

“By waiting a
minute, the evidence suggests that you can make a potentially enormous
difference to the prospects of these babies,” says Tarnow-Mordi.

“If we’d managed to
do this trial in five years instead of the eight or nine years it took, there might
be thousands more babies alive around the world, because that information would
have been available sooner rather than later.”

The more babies that are recruited to clinical trials, the sooner there is enough information to understand the health effects, and the sooner we can put important changes to health practice into our health systems.

Collaboration, not just consent

It can take 10 years or more to recruit enough babies into a clinical trial to make it scientifically valid. As shown in the APTS, this delay in recruitment could cost lives.

In 2014 a team led by Tarnow-Mordi’s colleague at UNSW,
Professor Ju Lee Oei, with Professor Ian Wright and Dr Javeed Travadi at the
University of Newcastle, were forced to abandon a pioneering clinical trial
called TORPIDO due to low numbers of participants enrolling.

But the value of TORPIDO
was that it raised the possibility that giving very preterm babies air rather
than pure oxygen at birth could be associated with lower survival.

This prompted the
team to reach out to Cruz to discuss ways to increase the number of babies
benefiting from clinical trials in the delivery room.

Gaining parents’
permission before birth is difficult. It’s not possible to predict early in a
pregnancy whether a baby will be born prematurely, so prospective parents may
think there’s little reason to enrol in a trial for preterm babies.

A research team
might need to get 200 signatures for every baby who is actually born preterm
and is eligible for the trial, which is not exactly feasible.

This means that hospital
staff must approach parents about clinical trials either in the delivery suite
or in the traumatic hours following their baby’s birth. Parents’ reticence to
participate is likely exacerbated by a lack of understanding of the various
phases of clinical trials.

“A lot of parents do have a fear that their babies are just going to be experimented on,” says Cruz. She explains that large consumer advocacy groups like Miracle Babies have the ability to quickly engage a network of parents who can share their own stories of being involved in clinical trials. This kind of education and awareness goes beyond just informing parents about which trials are happening – it’s about opening a conversation that helps alleviate certain fears.

Better outcomes for patients

The partnership
between Miracle Babies and researchers from UNSW, the University of Sydney, and
the University of Newcastle led to a different approach to consent for the recently
funded TORPIDO30/60 trial. This trial aims to compare two different
concentrations of oxygen, 30% and 60%, for the initial breathing support of
preterm babies.

“The only way we could
answer the question of whether to use 30% oxygen or 60% oxygen in the delivery
room as soon as the baby is born was to ask the Hunter
New England Research Ethics Committee to allow waiver of initial consent,
carefully following the National Statement on Ethical Conduct in Human Research
issued by NHMRC, the Australian Research Council, and the Australian
Vice-Chancellors’ Committee,” says Tarnow-Mordi.

He emphasises that the 30% and 60% oxygen levels are already within recommended practice, and pose no known risk compared with usual care. But there have been no clinical trials to determine whether starting breathing support with one of these oxygen levels has slightly better outcomes for the baby. 

Waiver of consent
means that all babies can benefit by entering the study, including those born
at night, on weekends, or in emergencies – a group that was often missing from
previous trials.

“When I spoke to
other mothers, it seemed to be like a no-brainer,” says Cruz. “This was a question
that hadn’t been answered for 30 years. These were treatments that were already
happening.”

The trial was
approved, and the ethics committee requested that all parents be informed about
the study in the days after birth.

“We probably
underestimated the impact that parents themselves can have in helping trials
happen,” says Tarnow-Mordi.

“I think what we’re
learning is that, if we include parents right from the very beginning, or even
before the trial has been designed, they are going to be extremely valuable and
powerful members of the team.”

He says the results
of the trial could be the difference between getting a reliable answer to a
critical question, and many more years of uncertainty.

“Recent evidence suggests that, on average, patients across all specialties have slightly better outcomes – including survival – by taking part in Phase III trials of different treatments, like TORPIDO 30/60, than by having usual care,” he adds.

“Our research team, in partnership with Miracle Babies Foundation and the Hunter New England Research Ethics Committee, plan to publish this experience so that others can be aware of it.”

By Viki Cramer