Lessons from Virtual Trials in time of a Pandemic: Minnesota - PowerPoint PPT Presentation

Lessons from Virtual Trials in time of a Pandemic: Minnesota Hydroxychloroquine experience David Boulware, MD, MPH, CTropMed Professor of Medicine University of Minnesota Oct 30, 2020 boulw001@umn.edu

Lessons from Virtual Trials in time of a Pandemic: Minnesota Hydroxychloroquine experience 1) post-exposure prophylaxis RCT (n=821) 2) preemptive early treatment RCT (n=491) 3) pre-exposure prophylaxis RCT (n=1483) David Boulware, MD, MPH, CTropMed Professor of Medicine University of Minnesota Oct 30, 2020 boulw001@umn.edu

3 June 2020 17 July 2020 17 Oct 2020

How did we do this? Lessons learned

Cryptococcal Meningitis Clinical Trials in Africa CROI HIV Conference March 9-12, 2020 Boston, MA

Great Team (with 4 days of free time: March 9-12)

Trial Design of Post-Exposure Prophylaxis Assumptions: Statistically Powered for 50% reduction in illness 10% illness rate of symptomatic infection 20% lost to follow up with internet based virtual trial

Trial Design of Post-Exposure Prophylaxis Actuality: Statistically Powered for 50% reduction in illness ~14% illness rate of symptomatic infection ~9.4% lost to follow up with internet based trial (n=77)

Two Stage RedCAP Survey 1) Screening  Email 2) Enrollment Verify Receipt of Medicine Patient Reported Outcomes Email or SMS w/ Twilio integration into RedCAP

Patient-Reported Outcomes (PROs) • Are you experiencing COVID-19 symptoms? – Checklist of symptoms, and free text. – Visual analog scale 0-10 of overall symptom severity • Since starting the study medicine, have you had any side effects? – Checklist of common HCQ side effects, and free text. • Have you been hospitalized since enrolling in this study? • D5 & D14 Targeted list of medicines (including zinc) • Day 14 assessed adequacy of blinding

Symptom Complex: Probable Cases Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Classification Final Case 1 1 1 1 1 1 1 1 1 1 1 1 Treatment 1 1 1 1 1 1 1 1 1 1 1 Group 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Cough 1 1 1 1 1 1 1 Fever Shortness of 1 1 1 1 1 1 1 Breath 1 1 1 1 1 1 1 1 1 1 1 1 Headache 1 1 1 1 1 1 1 1 1 1 1 Sore Throat 1 1 1 1 1 1 1 1 1 1 1 1 Fatigue 1 1 1 1 1 1 1 1 Myalgia 1 1 1 1 1 1 Anosmia 1 1 1 1 1 Diarrhea Nasal 1 1 1 1 Congestion 1 1 1 1 1 Rhinorrhea Other 1 1 1 1 1 1 1 1 Symptoms

Symptom Complex: Possible Cases Non-Case Non-Case Non-Case Non-Case Non-Case Non-Case Non-Case Non-Case Non-Case Non-Case Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Classification Final Case 2 2 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 1 1 1 1 1 1 Treatment Group Cough 1 Fever Shortness of Breath 1 1 1 Headache 1 1 1 1 1 1 1 Sore Throat 1 Fatigue 1 Myalgia 1 Anosmia 1 1 1 1 1 1 Diarrhea Nasal 1 1 1 1 1 Congestion 1 1 1 1 Rhinorrhea Other 1 1 1 1 Symptoms

U.S. Council of State and Territorial Epidemiologists: Probable COVID-19 Case Definition At least 1 of the following: OR • cough, Epidemiologic Linkage • shortness of breath, or • Clinically compatible symptoms with one or more of the following • difficulty breathing exposures in the 14 days before OR onset of symptoms. At least 2 of the following: • fever (measured or subjective), PCR False neg rate on first day • chills, of symptoms is 38% (CI: 20- • rigors, 65%) with serial testing. • myalgia, • headache, Kucirka LM et al. Annals of • sore throat, Internal Med. 2020 • new olfactory and taste disorder wwwn.cdc.gov/nndss/conditions/coronavirus-disease- 2019-covid-19/case-definition/2020/

Visual Analog Scale 10cm scale on paper 0-10 continuous scale in RedCAP Increment of 0.1 is captured Subjective measure Intra-person change over time. >50,000 publications for Visual Analog(ue) Scale

Screening, Consent, & Enrollment

Screening Surveys

Adherence Hydroxychloroquine Placebo P-value (N=414) (N=407) Reported Taking Any Study Medicine 349 (84) 351 (86) Reported 100% Study Medicine Adherence 312 (75) 336 (83) 0.01 Reasons Participants Did Not Take All Medication Study Medicine Side Effects 17 (4.1) 8 (2.0) Advised to not take Hydroxychloroquine 6 (1.4) 2 (0.5) Medicine not received from Fedex 9 (2.2) 2 (0.5) Took non-study Hydroxychloroquine 4 (1.0) 0 (0.0) Felt no longer at risk 5 (1.2) 3 (0.7) Other Reason 12 (2.9) 10 (2.5) Study not operating in a vacuum. Substantial media coverage during trial.

Automated RedCAP Survey • Two part enrollment – Screening #1; Consent & Enrollment #2 – Verified working email – Could not change answers • Screening: Used Branched RedCAP logic – Assessed inclusion/exclusion criteria – Most criteria were not publicly posted • Calculated hidden field variable to determine eligibility – If eligible, follow up email had URL for enrollment

– – – – – – RedCAP Branched Logic Green = Early Tx Blue = PEP No positive test No positive test Positive test (negative, not (negative, not White = None tested, pending) tested, pending) Symptoms within 4 Symptoms started days beyond 4 days HCW/First HCW/First HHC Non-HHC No known contact responders responders Symptoms started Symptoms within 4 Symptoms started Symptoms started Symptoms started Symptoms within 4 Symptoms within 4 beyond 4 days days beyond 4 days beyond 4 days beyond 4 days days days No symptoms -- No symptoms -- No symptoms -- No symptoms -- highest risk exposure highest risk exposure within 4 days with within 4 days with someone who has someone who has HHC Last saw been confirmed been confirmed Contact with positive positive Symptoms within 4 confirmed + within LAST contact within days and 2/3 (cough Contact not tested -- Contact not tested -- 14 days of HHC 4 days with someone fever, shortness of expert review expert review Contact test pending Contact test pending symptom start who has been breath) confirmed positive highest risk exposure within 4 days with someone who has been confirmed HHC Last saw HCW saw Contact with HCW saw Contact with positive Contact within 14 confirmed + within 14 days of confirmed + within 14 days of Contact test pending days of HHC HCW symptom start HCW symptom start or negative or no symptom start and known contact or contact now in ICU LAST contact within 2/3 (cough fever, 2/3 (cough fever, Contact + but time OR FIRST RESPONDER OR FIRST RESPONDER 4 days with someone shortness of breath) shortness of breath) from HHC last saw who is in the ICU and them and HHC has a pending test started symptoms is beyond 14 days Contact test pending Contact test pending or negative or no or negative or no highest risk exposure within 4 days with known contact or known contact or Contact + but time Contact + but time someone who is in the ICU from HCW saw them from HCW saw them and has a pending test and HCW started and HCW started symptoms is beyond symptoms is beyond 14 days 14 days

– – – – – – No positive test (negative, not RedCAP Branched Logic tested, pending) Green = Early Tx Blue = PEP No positive test Positive test (negative, not White = None tested, pending) HCW/First Symptoms within 4 Symptoms started responders days beyond 4 days Symptoms started Symptoms within 4 beyond 4 days days HCW/First HHC Non-HHC No known contact No symptoms -- responders highest risk exposure within 4 days with Symptoms started Symptoms within 4 Symptoms started someone who has Symptoms started Symptoms within 4 beyond 4 days days beyond 4 days beyond 4 days days No symptoms -- been confirmed No symptoms -- No symptoms -- positive highest risk exposure within 4 days with Contact not tested -- someone who has HHC Last saw been confirmed expert review Contact test pending Contact with positive Symptoms within 4 confirmed + within LAST contact within days and 2/3 (cough Contact not tested -- 14 days of HHC 4 days with someone fever, shortness of expert review Contact test pending symptom start who has been breath) confirmed positive highest risk exposure within 4 days with someone who has been confirmed HHC Last saw HCW saw Contact with HCW saw Contact with positive Contact within 14 confirmed + within 14 days of confirmed + within 14 days of Contact test pending days of HHC HCW symptom start or negative or no symptom start and HCW symptom start known contact or contact now in ICU LAST contact within 2/3 (cough fever, Contact + but time OR FIRST RESPONDER 4 days with someone shortness of breath) from HHC last saw who is in the ICU and them and HHC 2/3 (cough fever, OR FIRST RESPONDER has a pending test started symptoms is shortness of breath) beyond 14 days Contact test pending or negative or no highest risk exposure within 4 days with known contact or Contact + but time someone who is in the ICU from HCW saw them and has a pending test and HCW started Contact test pending symptoms is beyond or negative or no 14 days known contact or Contact + but time from HCW saw them and HCW started symptoms is beyond 14 days