Previous Collaborations

The ARREST trial was the first randomized clinical trial in the USA of extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation versus standard ACLS treatment in patients with out-of-hospital cardiac arrest (OHCA) and refractory ventricular fibrillation. The ARREST trial aimed to compare survival to hospital discharge between these two local standards of care, after arrival at the hospital. The ARREST trial used a Bayesian response adaptive randomization design and was terminated at the first interim analysis due to the overwhelming efficacy of ECMO-facilitated resuscitation over standard ACLS resuscitation.

PI: Demetris Yannopoulos

Funding: NIH R61-HL142696

Publications:

Yannopoulos D, Kalra R, Kosmopoulos M, Walser E, Bartos JA, Murray TA, Connett JE, Aufderheide TP. Rationale and methods of the Advanced R2Eperfusion STrategies for Refractory Cardiac Arrest (ARREST) trial. Am Heart J. 2020 Nov;229:29-39. doi: 10.1016/j.ahj.2020.07.006.

Yannopoulos D, Bartos J, Raveendran G, Walser E, Connett J, Murray TA, Collins G, Zhang L, Kalra R, Kosmopoulos M, John R, Shaffer A, Frascone RJ, Wesley K, Conterato M, Biros M, Tolar J, Aufderheide TP. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet. 2020 Dec 5;396(10265):1807-1816. doi: 10.1016/S0140-6736(20)32338-2.

The COVID-OUT trial was a phase 3, double-blind, randomized, placebo-controlled trial, to evaluate the effectiveness of three repurposed drugs — metformin, ivermectin, and fluvoxamine — in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The trial used an efficient 2-by-3 factorial design to facilitate estimating the main effect of each repurposed drug on the primary outcome — a binary indicator of hypoxemia by home oxygen monitoring (SpO2 < 94%), Covid-19 related Emergency Department Visit or Hospitalization, or Death through Day 14. A blinded sample size re-estimation was conducted accounting for vaccination uptake and its predicted reduction on the primary outcome event rate in the placebo arm.

PI: Carolyn Bramante

Funding: Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation

Publications:

Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Proper JL, Siegel LK, Klatt NR, Odde DJ, Luke DG, Anderson B, Karger AB, Ingraham NE, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A, Saveraid HG, Tordsen WJ, Pullen MF, Biros M, Sherwood NE, Thompson JL, Boulware DR, Murray TA; COVID-OUT Trial Team. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599-610. doi: 10.1056/NEJMoa2201662. PMID: 36070710.

Boulware DR, Murray TA, Proper JL, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Siegel LK, Klatt NR, Odde DJ, Karger AB, Ingraham NE, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A, Saveraid HG, Tordsen WJ, Pullen MF, Sherwood NE, Huling JD, Bramante CT; COVID-OUT study team. Impact of SARS-CoV-2 vaccination and booster on COVID-19 symptom severity over time in the COVID-OUT trial. Clin Infect Dis. 2022 Sep 17:ciac772. doi: 10.1093/cid/ciac772. Epub ahead of print. PMID: 36124697; PMCID: PMC9494422.

The Program for LUng Cancer Screening and TObacco Cessation (PLUTO) trial was a two-stage sequential randomized assignment randomized trial (SMART) to develop and inform adaptive intervention strategies for tobacco cessation delivered in the context of lung cancer screening. In phase 1, all participants received tobacco longitudinal care (TLC) with a minimum of monthly contact for one year, comprised of phone coaching and nicotine replacement therapy. PLUTO’s primary aim was to test the effect of phase 2 continued TLC vs. TLC+Medication Therapy Management (TLC+MTM) among incomplete treatment responders (any smoking in the last 7 days). MTM includes prescription smoking cessation medications (varenicline or

bupropion). Secondary aims tested the effect of continued TLC vs. TLC quarterly (TLC-Q) in phase 2 among complete treatment responders, and the effect of considering a transition to phase 2 at week 4 vs. 8.

PI: Anne Joseph

Funding: NIH R01-CA196873

Publications:

Fu SS, Rothman AJ, Vock DM, Lindgren B, Almirall D, Begnaud A, Melzer A, Schertz K, Glaeser S, Hammett P, Joseph AM. Program for lung cancer screening and tobacco cessation: Study protocol of a sequential, multiple assignment, randomized trial. Contemp Clin Trials. 2017 Sep;60:86-95. doi: 10.1016/j.cct.2017.07.002.

Joseph AM, Rothman AJ, Almirall D, Begnaud A, Chiles C, Cinciripini PM, Fu SS, Graham AL, Lindgren BR, Melzer AC, Ostroff JS, Seaman EL, Taylor KL, Toll BA, Zeliadt SB, Vock DM. Lung Cancer Screening and Smoking Cessation Clinical Trials. SCALE (Smoking Cessation within the Context of Lung Cancer Screening) Collaboration. Am J Respir Crit Care Med. 2018 Jan 15;197(2):172-182. doi: 10.1164/rccm.201705-0909CI.

The objective of the Prescribing Interventions for Chronic Pain using the Electronic health record (PRINCE) study is to assess the effects of two behavioral economics-informed interventions embedded within the electronic health record (EHR) on guideline-concordant pain treatment and opioid prescribing decisions in primary care settings. The PRINCE study uses a cluster-randomized 2 × 2 factorial design in 43 primary care clinics to test the effects of two interventions. One intervention alters the "choice architecture" within the EHR to nudge clinicians toward non-opioid treatments for opioid-naïve patients and toward tapering for patients currently receiving a "high risk" opioid. The other intervention integrates the prescription drug monitoring program (PDMP) directly within the EHR. An adaptive design allows for the possibility of secondary randomization to test if interventions can be titrated while maintaining efficacy.

PI: Ezra Golberstein

Funding: NIH R21DA046084, R33DA046084

Publications:

Vock DM, Neprash HT, Hanson AV, Elert BA, Satin DJ, Rothman AJ, Short S, Karaca-Mandic P, Markowitz R, Melton GB, Golberstein E. PRescribing Interventions for Chronic pain using the Electronic health record (PRINCE): Study protocol. Contemp Clin Trials. 2022 Oct;121:106905. doi: 10.1016/j.cct.2022.106905. Epub 2022 Aug 31. PMID: 36057376.

Neprash HT, Vock DM, Hanson A, Elert B, Short S, Karaca-Mandic P, Rothman AJ, Melton GB, Satin D, Markowitz R, Golberstein E. Effect of Integrating Access to a Prescription Drug Monitoring Program Within the Electronic Health Record on the Frequency of Queries by Primary Care Clinicians: A Cluster Randomized Clinical Trial. JAMA Health Forum. 2022 Jun 5;3(6):e221852. doi: 10.1001/jamahealthforum.2022.1852. PMID: 35977248; PMCID: PMC9168784.

SRCBST-1 was a phase 1-2 dose finding trial to evaluate the safety and efficacy of a novel targeted toxin for canine angiosarcoma. SRCBST-1 utilized a novel dose-escalation design that simultaneously evaluated safety and efficacy, while accounting for the delay in endpoint ascertainment resulting in a substantial decrease in trial duration.

PI: Jamie Modiano

Funding: National Canine Cancer Foundation AB15MN-002

Publications:

Koopmeiners JS, Modiano J. A Bayesian adaptive Phase I-II clinical trial for evaluating efficacy and toxicity with delayed outcomes. Clin Trials. 2014 Feb;11(1):38-48. doi: 10.1177/1740774513500589.

Borgatti A, Koopmeiners JS, Sarver AL, Winter AL, Stuebner K, Todhunter D, Rizzardi AE, Henriksen JC, Schmechel S, Forster CL, Kim JH, Froelich J, Walz J, Henson MS, Breen M, Lindblad-Toh K, Oh F, Pilbeam K, Modiano JF, Vallera DA. Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR. Mol Cancer Ther. 2017 May;16(5):956-965. doi: 10.1158/1535-7163.MCT-16-0637.