An Innovative Design Proposal for Investigating Long-Acting Growth Hormone Drug in A Single Master Protocol Across Multiple Indications with Single Hypothesis Test

For the past 30 years, the daily recombinant human growth hormone (rhGH) therapy such as Somatropin has been demonstrated to be safe and effective and has been widely used for pediatric growth hormone deficiency (pGHD) and other growth failure conditions in children. More recently, several long-acting recombinant human growth hormone (LAGH) have also been developed or are close to regulatory approval to decrease the inconvenience of daily injections and increase treatment adherence through once weekly administration. Somatrogon is an example of one such LAGH which was approved by FDA for pGHD indication in June 2023. A randomized Phase 3 study was conducted and demonstrated non-inferiority (NI) of Somatrogon compared to daily Somatropin for pGHD patients. It is of interest to study Somatrogon in other conditions involving growth failure in children. These include Small for Gestational Age (SGA), Idiopathic Short Stature (ISS), and Turner Syndrome (TS). All these conditions result in growth failure, albeit because of different etiologies. We propose a single study which utilizes a master protocol design that promotes efficiencies for the Sponsor, investigators, study participants, and regulatory agencies and a novel application of the meta-analysis across the multiple indications. This single master protocol approach provides the framework by which we are able to evaluate a common intervention across multiple indications in parallel, which is an innovative and efficient alternative to the standard series of clinical trials that typically investigate one intervention in a disease in a single study. The study design and statistical methodologies are described. Simulations are also presented to compare study power under different scenarios.