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Published on: September 20, 2019
Combined integrated protocol/basket trial design for a first-in-human trial
Ulla Derhaschnig1,2, Jim Gilbert3, Ulrich Jäger4
1Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Background:
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.
Results:
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.
Conclusions:
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.
Insights
This study introduces an innovative integrated protocol design for rare disease drug development, demonstrating pathway specificity as a viable approach for basket trials beyond oncology. The trial evaluated TNT009
Area of Science:
- Pharmacology
- Clinical Trial Design
- Immunology
Background:
- Innovative trial designs, including basket and integrated protocols, are crucial for rare disease drug development.
- These designs have primarily been used in oncology but are now being explored in other therapeutic areas.
- This study reports on a first-in-human integrated protocol design for rare complement-mediated disorders.
Purpose of the Study:
- To evaluate the safety and tolerability of TNT009, a novel monoclonal antibody targeting the C1s subunit of complement component C1.
- To demonstrate the feasibility of an integrated protocol design transitioning from healthy volunteers to patients with rare complement-mediated diseases.
- To explore pathway specificity as a paradigm for defining patient cohorts in basket trials.
Main Methods:
- A prospective, double-blind, randomized, placebo-controlled, first-in-human study.
- The trial included three parts: Phase Ia in healthy volunteers (parts one and two) and Phase Ib in patients (part three).
- Patients in part three had various complement-mediated diseases (bullous pemphigoid, antibody-mediated rejection, cold agglutinin disease, warm autoimmune hemolytic anemia) sharing a common pathophysiological mechanism.
Main Results:
- The study successfully evaluated the safety and tolerability of TNT009 in humans.
- The integrated protocol design facilitated the transition from healthy volunteers to patients with rare complement-mediated disorders.
- The trial involved a single cohort of patients with diverse complement-mediated diseases.
Conclusions:
- This trial presents a novel application of integrated protocol and basket trial designs outside of oncology.
- Pathway specificity, rather than single genetic aberrations, is a viable and potentially less restrictive paradigm for defining baskets in rare disease trials.
- This approach may serve as a model for future innovative drug development programs in rare diseases.
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