New Trial Seeks to Pin Down Pediatric PAH Treatment

A new phase 3 study comparing mono and duo therapies may yield greater guidance and treatment options for children with pulmonary arterial hypertension (PAH).

PAH is a rare condition in children, but is often fatal if left untreated, and protocols for pediatric patients have not been well-studied, according to Lewis H. Romer, MD, of Johns Hopkins University, Baltimore, the lead investigator of the study.

“The burden of morbidity and mortality of pediatric PH [pulmonary hypertension] is not acceptable at the present time, and it is important that we in the field focus on optimizing quality of life and longevity for our patients,” Romer said in an interview.

“Our hope is that the data from the Kids MoD PAH study (Mono or Duo Initial Therapy for Pediatric Pulmonary Arterial Hypertension) will inform the pediatric PAH community’s choice of initial therapy for children with PAH,” Romer said. “We also hope to provide information about possible clinical trajectories of disease with and without lung disease and about novel metrics for measuring functional progress of children with PAH,” he explained.

In practice, the clinical presentations of PH in children may vary widely and include fatigue, poor exercise tolerance, and syncope, said Romer. “Children may also present with failing to thrive or to grow properly and decreased performance in other areas of daily life,” he said. In addition, PH in newborns (a disorder known as persistent PH of the newborn) may become a life-threatening event in the first hours to days of life and may indicate other developmental issues in the lung and/or with circulation, Romer told Medscape Medical News.

Studies on adults with PH indicate that combination therapies are more effective than single drugs, but whether this holds true for children or for people of any age with PH caused by lung disease remains unknown, Romer said.

“If combination therapy is best for kids and for people with lung disease–associated PH, then it should be started as early as possible after initial diagnosis. If combination therapy is not the best way forward, then single drugs should be used in order to provide care that has fewer potential toxicities and is more cost-effective care,” he explained.

Children aged 3 months to 18 years may be eligible for the Kids MoD PAH study if they have symptomatic PH but are not in heart failure, Romer said. “Children meeting these criteria may be referred to a Pediatric PH center for screening for the Kids MoD PAH Study. Centers may be found at https://pphnet.org.”

The multicenter study is currently recruiting patients aged 3 months to 18 years who are treatment-naive but diagnosed with PAH. The study is designed to last 24 months, with clinical endpoints analyzed at 12 and 24 months. Patients will be followed with current standard of care assessments at recommended intervals.

The open-label design compares sildenafil (Viagra) alone with a combination of sildenafil and bosentan, and the primary endpoint is World Health Organization functional class (FC) at 12 months after the start of the therapy.

The study protocol was published in Pulmonary Circulation in 2023. Dosing will be informed by pediatric case series, AHA/ATS guidelines, the European Medicines Evaluation Agency pediatric guidelines, a previously published systematic review, and clinical experience, the researchers wrote in the protocol.

The study includes 12 sites, with Johns Hopkins University serving as the Clinical Coordinating Center and Duke University serving as an independent Data Coordinating Center. The facilities will collaborate on maintaining data integrity, reporting adverse events, conducting analyses, and disseminating findings, according to the protocol.

Clinical Challenges, Cautious Optimism

Pediatric PAH is significant, complex, and distinct from PAH in adults, said Anjali Vaidya, MD, co-director of the Pulmonary Hypertension, Right Heart Failure & CTEPH Program at Temple University Hospital, Philadelphia, in an interview.

“While it may be idiopathic, it is often associated with developmental lung disorders, congenital heart conditions, hereditary, or toxin-induced causes,” said Vaidya, who is not involved in the upcoming study. “The unique pathophysiology and prognosis are crucial to understand how to approach medical therapy options specifically to these associated conditions in pediatric patients,” she said. Studies are needed to explore medication dosing, adverse effects and tolerability, safety, and long-term risks, she added.

“A challenge regarding research in this condition is that even within the rare group of pediatric patients that have PAH, there are several distinct subgroups that represent very different underlying pathophysiologic conditions,” Vaidya told Medscape Medical News. “Taken together, along with idiopathic and other causes of PAH, the heterogeneity in disease mechanisms and phenotypes makes clinical trial research challenging to design, adequately enroll large numbers of patients, and interpret data from,” she said.

However, “The approach to treat PAH with upfront combination therapy has great potential,” Vaidya said. Real-world clinical experience supports adequate safety in pediatric patients being on both the medications in this study, sildenafil and bosentan, she noted. Studying the potential benefit of using both medications up front, rather than sequentially, may reveal data that could guide practice and yield greater and earlier clinical benefit in treatment of pediatric PAH, she added.

Since the publication of the AMBITION study in 2015, upfront combination therapy with tadalafil and ambrisentan has been the standard of care for adults with PAH, said Vaidya. This change had driven a more progressive approach to PAH in adults, with higher clinical standards for achieving lower clinical risk, and this potential may follow in the pediatric PAH population, she said.

“If this study yields promising results, it will be a stepping-stone to further research to build on regarding combination medical therapy in pediatric PAH,” Vaidya told Medscape Medical News. “Currently, in the United States, bosentan and sildenafil are approved by the FDA for use in pediatric patients. However, in Europe, another endothelin receptor antagonist (ambrisentan), PDE5 [phosphodiesterase 5]-inhibitor (tadalafil), and a soluble guanylate cyclase stimulator (riociguat) are also available and approved by the European Medicines Agency (EMA) for pediatric use. Studying additional therapies in combination will be crucial to allow for greater options across the world for pediatric PAH,” she said.

Looking ahead, the Kids MoD PAH study may inform other randomized studies in pediatric PAH, such as additional combinations of medical therapies across the classes of PDE5-inhibitor or soluble guanylate cyclase with endothelin receptor antagonist, Vaidya noted. “If it is a positive study, it could inform future randomized clinical trial design to consider earlier addition of prostacyclin pathway agents (epoprostenol, treprostinil, selexipag) or activin binder (sotatercept) therapy initiated earlier on the backdrop of upfront combination therapy,” she said.

Although the primary endpoint of the current study is FC, additional secondary endpoints including cardiac parameters by imaging and biomarkers may continue to be incorporated in composite endpoints in future clinical trial designs, Vaidya said.

For more information, visit the study site on clinicaltrials.gov.

The Kids MoD PAH trial is supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Vaidya had no financial conflicts to disclose.