When results were released last July of a promising study on nitric oxide therapy for low-weight newborns, few outside of the University of Alabama at Birmingham (UAB) and the University of Colorado knew the barriers that were overcome to reach their conclusion. Like other trials, the back story might not have a long-term impact on anyone who wasn't there. But it does make patients and clinicians more appreciative of researchers' work.
The study, which took nine years from conception to completion, was published July 26 in the New England Journal of Medicine. It found nitric oxide therapy to be effective in significantly lowering the risk of long-term lung and brain injury in some premature and low birth weight infants.
UAB researchers, led by Gary Cutter, PhD, worked with neonatologist Dr. John Kinsella of the University of Colorado and others to investigate nitrous oxide's effectiveness for babies at high risk for delayed growth, breathing difficulties, neurological problems and other complications. The National Heart, Lung, and Blood Institute's data and safety monitoring committee oversaw the national study involving 793 newborns of 34 weeks of gestational age or less.
The results showed no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo. But for infants with a birth weight between 1000 and 1250 grams, the therapy did reduce the incidences of bronchopulmonary dysplasia and the overall risk of brain injury.
How will this study affect standard treatment? The jury is still out. Another trial is being conducted in Europe. Children in the UAB study will be monitored until they are at least two years old.
Although the study was designed to help overcome low-weight babies' survival and growth barriers, other barriers were overcome just to complete the study. Cutter, a biostatistics professor, agreed to run and design the multicenter study because he was intrigued by its possibilities. Always on the lookout for promising projects and with experience in maternal, fetal and neonatal work, Cutter agreed to coordinate this trial.
"I'm like a hammer looking for a nail," Cutter said of his fascination with study. When evaluating a trial's value, Cutter said, "We look for a question that has equipoise."
Cutter seeks studies balanced with questions and possible answers, not assumptions awaiting approval. He said a formal clinical trial gives clinicians objective information so patients can weigh therapy benefits and risk.
This trial's challenge was that infants can't weigh risks. And the parents, who were asked to participate within hours of their baby's unexpected arrival, were often not able to clearly think through the process.
Patient consent was further complicated by the emergence during the study of HIPAA regulations, which provided paperwork barriers hampering recruitment. Parents were further intimidated and less likely to participate.
If that wasn't enough, the start of the study, following its stringent funding review, coincided with Sept. 11, 2001. The Interstate Commerce Commission then changed its rules on the transportation of large tanks, initiating new labeling requirements. Some tanks were nitrous oxide. Others were placebos. The tanks had to remain unlabeled so test physicians and staff could remain "blind," without actions altering outcome.
A compromise was reached, with "Nitrous Oxide or Placebo" placed on the tanks so trials could proceed.
Meanwhile, Kinsella, Cutter's Colorado partner, was one of the physicians conducting the tests. He purposely stayed uninformed as the years passed and results were tallied in Birmingham. His awareness of possible outcomes might influence his test administration. For more than five years he treated his patients, not knowing whether preliminary results showed improvement.
Meanwhile, another study was stopped under fear of increasing brain bleeds. But after review, the National Heart, Lung, and Blood Institute told the UAB study to proceed. Later study showed that the other trial did not significantly increase brain bleeds after all.
It wasn't until August 2005 that Kinsella flew to Birmingham for the results. Some infants were still in the study, but the advantages of the treatment to a portion of the population were clear.
Cutter is unsure what evidence the Food and Drug Administration will need to license the very expensive therapy. Off-label use will not generally be reimbursable through insurance companies. But he believes the study will be useful and the hard work of the researchers — who worked many extra hours without additional reimbursement — will pay off.
"There's always uncertainty about a treatment," Cutter said. "But we're trying to help clinicians make the most informed decisions they possibly can. We need to be skeptical — and that's opposed to being cynical — and test through rigorous, objective collection of information."
January 2007
