title: Combined integrated protocol/basket trial design for a first-in-human trial.
abstract: Innovative trial designs are sought to streamline drug development in rare diseases. Basket- and integrated protocol designs are two of these new strategies and have been applied in a handful oncologic trials. We have taken the concept outside the realm of oncology and report about a first-in-human integrated protocol design that facilitates the transition from phase Ia in healthy volunteers to phase Ib in patients with rare complement-mediated disorders driven by the classical pathway.
  
  
  
  We have been conducting a prospective, double-blind, randomized, placebo-controlled first-in-human study with TNT009, which is a humanized monoclonal antibody directed against the C1s subunit of human complement component C1. The trial consisted of three subparts, including normal healthy volunteers (part one and two) and a single cohort of patients in part three. Patients suffered from various complement-mediated diseases sharing the same pathophysiological mechanism, i.e. bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune hemolytic anemia. Primary objective of the trial has been to evaluate the safety and tolerability of TNT009 in humans.
  
  
  
  This trial provides probably the first example that basket trials may not be limited to single genetic aberrations, which is overly restrictive, but our trial design demonstrates that pathway specificity is a viable paradigm for defining baskets. This will hopefully serve as a role model that could benefit other innovative drug development programs targeting rare diseases.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.|Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Ulla
authors.initials: U
authors.lastname: Derhaschnig
authors.affiliation: True North Therapeutics, San Francisco, CA, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Department of Internal Medicine I, Division of Haematology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.affiliation: Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Böhmig
authors.affiliation: Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. bernd.jilma@meduniwien.ac.at.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D011446:Prospective Studies; D035583:Rare Diseases / Q000188:drug therapy*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C000623343:TNT009
keywords: Basket design; Complement pathway; First-in-human trial; Integrated protocol design; Orphan disease