Designing the Right Clinical Trial to Yield the Greatest Value

A Registration Trial May Provide Data For Approval, But Is It Sufficient To Answer Treatment Decisions From Healthcare Providers And Payors?

Designing the Right Clinical Trial to Yield the Greatest Value

ByDavid Melnick, MD  and Cristina Larkin  

January 7th, 2019

In today’s health care environment, a randomized, well-controlled trial must not only meet the requirements for approval, but just as importantly, it must encourage early physician use and provide payors a justification for payment. Today, we announced positive feedback from our pre-Phase 3 FDA meeting for SPR994 for the treatment of complicated urinary tract infection (cUTI), which confirms our belief that positive results from a single Phase 3 clinical trial of SPR994 in cUTI designed as an all-oral SPR994 regimen versus IV standard of care and demonstrating a 10% non-inferiority margin would support the approval of SPR994 for the treatment of cUTI.  

We believe the trial design for our planned Phase 3 clinical trial meets the requirements for FDA approval and has the potential to provide compelling data to physicians and payors alike. We have submitted an Investigational New Drug (IND) application for SPR994 in cUTI and begun startup activities for our Phase 3 clinical trial. 

At Spero, we designed our planned SPR994 Phase 3 trial, ADAPT-PO, based on the FDA’s written guidance and feedback from healthcare providers to incorporate both clinical and economic rationale for use in trial design. The Phase 3 program is comprised of a single double-blind trial that compares our oral carbapenem, SPR994, head-to-head against the existing standard of care IV carbapenem antibiotic, ertapenem, in approximately 1,200 patients.  

Clinical data for prescribers: Given the high rate of infections that are resistant to all oral therapies, SPR994 has the potential to fulfill a critical need by enabling patients to transition from the hospital earlier (“Go Home”) or avoid hospitalization altogether (“Stay Home”).  We spoke with over 100 healthcare providers and the consensus was that their decision on whether to deploy SPR994 to fill this unmet need would be predicated on robust data demonstrating that an oral antibiotic can achieve the same outcome as an IV antibiotic. ADAPT-PO is designed to speak to this question, as it will compare oral SPR994 with IV ertapenem to assess whether oral SPR994 offers microbiological coverage, safety and tolerability similar to the IV standard of care. This design is particularly strong because it focuses only on the population set that currently cannot benefit from existing oral therapy. In addition, by eliminating the need for an IV lead-in, ADAPT-PO’s trial design isolates the effects of the oral therapy on the infection.  Other trial designs are confounded by the presence of an IV therapy prior to the oral therapy being dosed.      

Economic data for payors: On the economic side, we spoke with payors covering more than 100 million U.S. lives and the key takeaway from those discussions is that hospitals and payors in general are placing increased emphasis on reducing unnecessary admissions and emergency department visits, as well as reducing length of stay and readmissions. With an average total cost of $10,741 to treat a patient with cUTI, which is only partially covered by an average DRG payment of $7,083, hospitals are financially incentivized to reduce unnecessary hospital exposure.1,2 Managed care payors also save money when patients are treated outside of the hospital or when patients are discharged on optimized regimens that reduce costs and readmissions. Given the wide availability of cheap, generic IV therapies, the effectiveness of the oral component of a regimen is key to justifying the value of a therapy and its ability to reduce hospital exposure. Demonstrating with robust evidence that the oral component of a cUTI treatment regimen can drive favorable outcomes is important to the economic justification for SPR994.  

 

      If ADAPT-PO is able to demonstrate that an oral therapy can produce substantially equivalent outcomes to the existing standard of care IV therapy in cUTI, we believe SPR994 has the potential to change the treatment paradigm by helping to get patients with cUTI out of the hospital sooner (“Go Home”) and keeping them from entering the hospital in the first place (“Stay Home”). Preventing hospitalization is a significant value to patients, payors and healthcare providers. Helping to alleviate exposure to the hospital setting by ensuring confidence in oral therapy has been well established within other therapeutic categories such as analgesics, COPD, and asthma and within antibiotics for the treatment of left sided endocarditis with the non-inferiority outcome shown in the POET study.3 At Spero, we look forward to executing on our planned pivotal SPR994 Phase 3 trial with the goal of changing the course of treatment for patients with cUTI.

About the Author(s):

David Melnick, MD

Chief Medical Officer of Spero Therapeutics

Cristina Larkin

Chief Operating Officer of Spero Therapeutics

Sources: 
1. Cost of Treatment and Reimbursement:  MacVane SH, Tuttle LO, Nicolau DP. Impact of Extended-Spectrum b-Lactamase–Producing Organisms on Clinical and Economic Outcomes in Patients With Urinary Tract Infection. J Hosp Med. 2014 Apr;9(4):232-8.
2. Nguyen H. Hospitalist to home: Outpatient parenteral antimicrobial therapy at an academic center. Clinical Infectious Diseases 2010; 51(S2):S220–S223.
3. POET:  IVERSEN, K. ET AL. “PARTIAL ORAL VERSUS INTRAVENOUS ANTIBIOTIC TREATMENT OF ENDOCARDITIS”, NEJM, AUGUST 28, 2018, HTTPS://WWW.NEJM.ORG/DOI/FULL/10.1056/NEJMOA1808312