>>LET ME WELCOME YOU TO THE 25TH LECTURE IN OUR COVID SCIENTIFIC INTEREST GROUP LECTURE SERIES. IT IS AN EXTRAORDINARY PLEASURE TO HAVE DR. PETER HORBY JOIN US TODAY FROM ERGO. PETER HORBY IS REALLY A MAN WHO NEEDS NO INTRODUCTION BUT I WILL DO ONE ANYWAY BECAUSE THIS IS HOW I JUSTIFY MY SALARY. HE IS -- HE RECEIVED HIS BSC IN HISTORY OF MEDICINE AT OXFORD IN 1989. AND THEN GOT HIS MBBS HIS DTMH AND Ph.D. ALL AROUND MEDICINE AND THEN STUDY OF EPIDEMICS IN PARTICULAR AROUND FLU AND AVIAN INFLUENZA. HE HAS GONE ON TO LEAD AN EXTRAORDINARY NUMBER OF PROJECTS THAT HAVE REALLY CHANGED THE PERCEPTION WE HAVE OF EPIDEMICS AND OF DISEASE. I THINK HIS STUDY OF HISTORY OF MEDICINE AS HE WAS MENTIONING BEFORE REALLY HAS GIVEN HIM A PERSPECTIVE, SADLY A LONG TERM PERSPECTIVE ON TRAGIC OUTCOMES THAT I HOPE HE WILL GO ON TO SHARE WAS. -- WITH US. HE IS CURRENTLY DIRECTOR -- HE ESTABLISHED AND IS THE DIRECTOR OF THE EPIDEMIC RESEARCH GROUP O FORD OR ERGO. AND -- OXFORD OR ERGO AND HAS BEEN LEADING THESE ACTIVITIES AROUND THE WORLD. AS HE POINTS OUT IN THE HUNDRED DAYS OF THIS EPIDEMIC, THE EARLY HUNDRED DAYS, HE WAS ABLE TO MAKE THREE REALLY GROUND-BREAKING CONTRIBUTIONS TO HOW WE THINK ABOUT AND TREAT THIS DISEASE. TO DISPROVE THE VALUE OF HYDROXY HYDROXYCHLOROQUINE AND SHOW THE VALUE OF DEX METH ZONE, THINGS THAT CHANGE HOW WE APPROACH THIS DISEASE. HE CURRENTLY LEADS THE RECOVERY NETWORK, RECOVERY TRIAL WHICH HE'LL SPEAK ABOUT TODAY AND THAT CURRENTLY HAS 300,000 PATIENT RECORDS IN 42 COUNTRIES, AN EXAMPLE OF THE INCREDIBLE ABILITY TO CREATE COLLABORATION AROUND WORLD THAT PETER WILL TALK TALK TO US ABOUT TODAY SO I'LL STOP THERE AND SAY THANK YOU FOR JOINING US, WE LOOK FORWARD TO YOUR PRESENTATION. >> THANK YOU, HAPPY TO TRY TO LIVE UP TO THE EXPECTATIONS. I'M ALSO THE EXECUTIVE DIRECTOR OF ISARIC, THAT HAS THE CLINICAL DATABASE, SO THAT 350,000 COVID PATIENTS FROM OVER A HUNDRED COUNTRIES. TODAY I WILL TALK ABOUT THE RECOVERY TRIAL I'M CO-CHIEF INVESTIGATOR OF WHICH IS ABOUT 37,000 PATIENTS AS A TREATMENT TRIAL. FOR COVID-19. SO YOU HAVE HEARD THESE WORDS CALL FOR GLOBAL ACTION AS OUTBREAK SPREADS, SOMETHING THAT WITH FEAR AND ANTICIPATION TO DO RESEARCH IN THESE AREAS. THIS WAS ACTUALLY GOING BACK TO 2009. YOU CAN SEE THE QUALITY OF UK NEWSPAPERS P WITH SOME OF THE HEADLINES ABOUT KILLER FLU IS HERE AND SWINE FLU. AND I JUST WANT TO REFLECT IN ONE SLIDE ABOUT OUR PAST ACHIEVEMENTS, IN H CLINICAL RESEARCH AND INFECTIOUS DISEASE. THIS SLIDE SHOW IT IS CLINICAL TRIAL AMBITIONS IN 2009, PANDEMIC INFLUENZA. THIS WAS A THING WE NEW WAS COMING AND SHOULD HAVE BEEN PREPARED FOR. SO IF YOU LOOK TO THE TRIALS REGISTERED IN CLINICALTRIALS.GOV, RANDOMIZED CONTROL TRIALS GOING TO DO TREATMENT EVALUATIONS, OVER 6,000 PATIENTS ANTICIPATED TO BE ENROLLED IN THE TRIALS IN 2009 PANDEMIC. ACTUALLY THE NUMBER OF PATIENTS ENROLLED WAS FAR LOW, IT WAS LESS THAN 1500 PATIENTS WHO ACTUALLY ENROLLED. LOOK AT THE ACTUAL NUMBERS WHEN RESULTS WERE PUBLISHED, IT WAS A COUPLE OF HUNDRED. NONE OF THAT DATA IS PUBLISHED DURING THE PANDEMIC, THAT LASTED A YEAR. SO PRETTY APPALLING TRACK RECORD 2009. I LIKE TO CALL IT EPIDEMIC CURVE OF AMBITION WHERE FAMILIAR LOOKING CURVE, WE HAVE IDEAS TRANSLATING TO SOME PROTOCOLS, AND WITH PATIENTS NO EVIDENCE, WE SEE THAT TIME AND AGAIN SO WE DIDN'T WANT TO REPEAT THIS THIS TIME AROUND, THAT'S WHAT WE CAN WORKING FOR SINCE 2009 SIMILAR PROVE THE RESEARCH INFRASTRUCTURE AND METHODOLOGIES WE USE FOR EPIDEMIC INFECTIONS. SO REALLY WE WANTED TO CHANGE THE CURVE AMBITION SO THAT PERHAPS A BIT LESS AMBITIOUS ABOUT IDEAS BUT WE TRANSLATE THOSE IDEAS THROUGH INTO EVIDENCE. SO WHOLE WORLD MUST TAKE ACTION. THIS TIME IT IS THE CURRENT PANDEMIC. BUT YOU CAN SEE IN THE NINE YEARS CERTAINLY CAUSE OF THE UK NEWSPAPERS HASN'T IMPROVED AT ALL. CALLING IT THE KILLER SNAKE FLU, WHEN IT FIRST ARRIVED. ANOTHER THING THE PAPERS GET WRONG. SO PAPERS DIDN'T IMPROVE, DID THE RESEARCH RESPONSE IMPROVE. SO WHEN WE STARTED WORKING ON THIS, WE HAD EXPERIENCE IN PREVIOUS OUTBREAKS AND WE KNEW THIS WAS GOING TO BE A CHALLENGE, WE KNEW IT WOULD BE A CLINICAL CHALLENGE, THE HEALTH SERVICE WOULD LIKELY BE OVERSTRETCHED, THERE WOULD BE HUGE TIME PRESSURES AND PERSONAL STRESSES FRONT LINE MEDICAL STAFF AND WE HAVE CERTAINLY SEEN THAT. AND LARGE NUMBERS OF UNWELL ANXIOUS PATIENTS, EARLY DATA CONTAINS WUHAN. ALSO THERAPY UNCERTAINTY. MANY CANDIDATES WE SAW THAT IN THE EBOLA AND OTHER OUTBREAKS A SLEW OF SENSIBLE AND CRAZY IDEAS AS WELL BEING PROPOSED. MANY OPINIONS AND VERY LITTLE DATA, A LOT OF PATIENT REPORTS UNCONTROL CASE SERIES IN TRIALS SO WE WANTED TO MAKE SURE WE HAVE A TRIAL THAT WAS FUNCTIONING IN THIS ENVIRONMENT. IF YOU LOOK AT WHAT THE EARLY RESPONSE WAS, THIS IS A REVIEW OF TRIALS REGISTERED, THIS WAS I THINK THIS WAS FROM THE -- LAST YEAR. 294 RCTs, REGISTERED IN THAT TIME AND IF YOU LOOK IN THE SECOND PANEL BELOW, THE SAMPLE SIZE WAS GENERALLY VERY SMALL. ANTICIPATED SAMPLE SIZE WAS LOW AS 50 MILLION COUPLE OF HUNDRED SO QUITE SMALL TRIALS. IT IS UNDERSTANDABLE TO HAVE SMALL TRIALS WHEN YOU HAVE DISEASE BUT PANDEMIC IT'S NOT GOING TO BE A RARE DISEASE, YOU DON'T NEED A SINGLE TRIAL YOU CAN HAVE ADEQUATELY POWERED TRIAL, TRADITIONAL TRIAL. JUST TO PUT IN PERSPECTIVE IF YOU LOOK AT THE SAMPLE SIZE, ROUGHLY I'M NOT A STATISTICIAN BUT THE EVENT RATE AND STANDARD OF CARE OBVIOUSLY WHATEVER YOU ARE, AGAIN YOUR COUNTING, TOTALITY, THE RISK OF GOING ON TO MECHANICAL VENTILATION, IT WAS 20%, 25% RISK REDUCTION. THEN YOU WOULD NEED NEARLY 2000 PATIENTS IF YOU WANTED TO HAVE ADEQUATE POWER WITH ADEQUATE P VALUE. MANY OF THE TRIALS WERE POWERED ON UNREALISTIC EVENT RATES AND UNREALIST I -- UNREALISTIC RISK REDUCTIONS. SO THESE ARE THE PRINCIPLES. WE WANTED TO BE QUICK, WE KNEW WE HAD TO BE QUICK. WE HAVE SEEN IN THE PAST THAT IF YOU DON'T ACT QUICKLY YOU JUST ARE TOO LATE AND YOU MISSED THE BOAT, YOU HAVE A TRIAL WITH NO PATIENTS. IT MUST BE BIG, WE WANTED IT TO BE BIG BECAUSE WE KNEW IT WAS GOING TO BE A PANDEMIC, WE KNEW THERE WAS GOING TO BE CASES PROBABLY AND WE KNEW FROM OUR EXPERIENCE WITH VIRUS INFECTION, THERE IS LIKELY A BIG SINGLE WIN PEOPLE TELL YOU MIRACLE CURE OUT THERE, THERE GENERALLY WRONG. WONDERFUL BENEFITS ARE PLAUSIBLE BUT NOT MASSIVE BENEFITS BUT MODERATE BENEFITS ARE WORTHWHILE. AT THE TIME WE WERE THINKING ABOUT THIS, IT ONLY TOOK 1500 DEATHS AND IF YOU CAN REDUCE THAT BY A FIFTH, 20% YOU SAVE 3,000 LIVES IN A PANDEMIC AFFECTS WORTHWHILE AND WHAT WE CAN EXPECT AND ALSO SMALL TRIALS THAT -- I HAVE RUN MORE TRIALS AND DELIBERATELY, I HAVE SEEN THE IMPACT OF (INAUDIBLE). SO IT MUST BE QUICK, MUST BE BIG, MUST BE SICKLE BECAUSE PEOPLE WILL BE OVERWHELMED IF IT'S NOT SIMPLE, PATIENTS JUST WANT TO BE ENROLLED. SO ALL THE MATERIALS ONLINE WE DESIGN THIS SO WE WOULDN'T HAVE TO DO SITE VISITS BECAUSE TRAVEL MAYBE RESTRICTED AND ENTRY TO HOSPITAL MAYBE RESTRICTED ALL THOSE THINGS DID TURN OUT TO BE TRUE. SO EVERYTHING IS AVAILABLE ONLINE AND WE GET A LOT OF INFORMATION REQUESTS ABOUT THE TRIAL AND WE DIRECT ALMOST EVERYBODY TO THE TRIAL WEBSITE BECAUSE EVERYBODY IS THERE, ALL THE REGULATED DOCUMENT, ALL THE VIRTUAL CONTROL, ALL THE LETTERS ALL THE DMC LETTERS. EVERYTHING IS THERE. AND THIS TYPE TRAINING IS REMOTE SO WE DON'T GO ON SITE RAINING PROTOCOL DELIBERATELY SPECIFIED THIS SHOULD BE CARRIED OUT BY MEDICAL STAFF ATTENDING PATIENT WHOSE ARE ADEQUATELY TRAINED, TO DELIVER A SIMPLE TRIAL AND MEASURE SIMPLE OUTCOMES, ALL THE TRAINING WAS ONLINE SO THERE WERE VIDEOS MADE AND PEOPLE WATCHED VIDEOS AND THEN THEY DIGITALLY RECORDED THE SIGNATURE THEY HAD SEEN, WE HAVE THE RECORD OF EVERYONE WHO RECEIVED IS TRAINING. VERY SIMPLE PATIENT INFORMATION, PATIENTS FROM SICK PATIENTS SO WE KEPT IT SIMPLE, TWO PAGES AND VERY SIMPLE CONSENT, AGAIN, TWO PAGES. WEB BASED RANDOMIZATION, WEB-BASED VERY SIMPLE ONLINE RANDOMIZATION FORM, REALLY REQUIRES ONLY ESSENTIAL DATA ELIGIBILITY FOR TRIAL, BASIC CHARACTERISTICS OF THE PATIENT, SUITABILITY FOR VARIOUS STUDY DRUGS AND AVAILABILITY OF STUDY DRUGS AND PERSON FILLING THE FORM. THE SUITABILITY AND AVAILABILITY IS IMPORTANT, THIS IS ADAPTIVE TRIAL AND NOT ALL DRUGS WILL BE AVAILABLE ALL SITES ALL THE TIME. EXAMPLE CONVALESCENT PLASMA, AVAILABLE AT ALL SITES AND SOME PEOPLE MAY NOT BE SUITABLE FOR SOME OF THE DRUGS SO YOU HAD TO CLICK -- ALL THE DRUGS IN THE TRIAL YOU HAD TO CLICK FOR EVERYONE, WAS IT AVAILABLE AND WAS IT SUITABLE. ONLY THEN WOULD YOU BE RANDOMIZED TO THAT COMPARISON. CONTROL FOR DRUG THAT WAS NOT AVAILABLE OR NOT SUITABLE FOR YOU. SO ONLY ONCE THAT'S BEING TESTED THAT YOU CAN BE RANDOMIZED TO THAT CONTROL FOR THAT SO YOU HAVE COMPARABLE GROUPS. A SIMPLE ONLINE FOLLOW-UP FORM, WHICH TREATMENTS DID THE PATIENTS RECEIVE BOTH THE TREATMENT IN TRIAL BUT ALSO TREATMENTS NOW ARE RELEVANT SO WE NEVER HAD REMDESIVIR IN THE TRIAL BUT WE HAVE REMDESIVIR, COVID 19 TEST RESULT, USE OF ORGAN SUPPORT, BUT WE DO HAVE THE OPPORTUNITY LINKAGE NATIONAL DATA SOURCES SO HUGE EFFORT GONE INTO LINKING OUR DATA UP TO NATIONAL DATA SYSTEMS, WHICH IS MADE A BIG DIFFERENCE BECAUSE IT MEANS WE HAVE 100% (INAUDIBLE) MOST OUTCOMES AND WE HAVE PERMISSION TO FOLLOW-UP DIGITALLY FOR TEN YEARS. THIS SHOWS YOU THE AMOUNT OF DATA WE HAVE. WE HAVE DATA TO ALL HOSPITALIZATION DATA SETS, ACROSS -- SO WE KNOW WHAT PATIENTS FOR WHAT PROCEDURES THEY HAD. WE HAVE LINKAGE NATIONAL DATA SETS SO YOU CAN'T DIE IN THE UK WITHOUT BEING REGISTERED SO THE LEGAL REQUIREMENT WE HAVE EVERY TWO WEEKS WE GET EVERY SINGLE PATIENT DEATH RECORD. WE HAVE LINKAGE TO DISEASE DATA SETS REALLY REGISTRY CANCER REGISTRY, PRIMARY CARE DATA SETS, WE HAVE ACCESS TO NATIONAL INTENSIVE CARE ALL THE DATABASE SO WE KNOW WHAT PATIENTS END UP IN ICU AND WHERE THEY WERE VENTILATED. AND WE ALSO HAVE LINKAGE TO THE NATIONAL COVID-19 TESTING DATABASE. SO WE CAN CROSS CHECK EVERYBODY'S COVID-19 DIAGNOSIS. SO IMPLEMENTATION. WE DID -- IT WAS A SIMPLE PROTOCOL, A LOT OF BACK END WORK WITH DATA LINKAGE AND RANDOMIZATION VERY SIMPLE PROTOCOL OTHERWISE. ACTUALLY BASED ON THE ISIS PROTOCOL FROM TREATMENT IN CARDIOVASCULAR DISEASE IN THE '80s SO WE HAD OUR FIRST SUBMISSION ON THE 13TH OF MARCH AND GET APPROVED SIX DAYS LATER. YOU CAN SEE AS WE ADDED TREATMENTS THE TURN AROUND TIME HAS BEEN VERY, VERY QUICK TO GET THESE THROUGH ETHICSES NHRD IS THE REGULATING AUTHORITY, LIKE THE FDA, IT IS THE RESEARCH ETHICS COMMITTEE, REC IS A NATIONAL STRUCTURE SO ONE NATIONAL ETHICS COMMITTEE APPROVED FOR THE (INAUDIBLE) SO THAT WAS A VERY EFFICIENT PROCESS. SO THIS IS THE FIRST WAVE OF THE OUTBREAK IN THE UK. AND WE GOT THE GREEN LIGHT SO WE WENT TO TALK TO THE CHIEF MEDICAL OFFICER AND TOLD HIM WHAT WE WERE PROPOSING TO DO. AND HE GAVE US THE GREEN LIGHT ON THE 10TH OF MARCH, HE SAID DO IT. THIS IS WHAT WE WANT. WE MANAGED TO INCLUDE THE FIRST PATIENT NINE DAYS LATER IN OXFORD SO WE WENT OUT TO THE -- AND JUST NINE DAYS LATER WE ADMINISTERED TO FIRST PATIENT. WE HAD UPSWING WITH THE OUTBREAK WHICH IS WHAT WE WANTED TO DO, WE KNEW THERE WAS URGENCY. SO WE HAD TO RECRUITED A THOUSAND PATIENTS, WITHIN TWO WEEKS. 5,000 IN A MONTH AND NEARLY 10,000 IN TREATMENT SO MANAGED TO CATCH THE FIRST WAVE OF THE EPIDEMIC. THIS SHOWS YOU THE FIRST HUNDRED DAYS, SO ON THE LEFT IS UNITED KINGDOM, IN EACH OF THOSE GREEN BLOBS IS A HOSPITAL AN SIZE OF THE BLOB IS THE NUMBER OF RECRUITS, SO YOU CAN SEE WE MANAGED TO NOT ONLY NATIONALLY ACROSS 175 HOSPITALS WHICH MEANT WE CAN GET QUICK RECRUITMENT. ON THE RIGHT DARK RED LINE IS PRIMARY RANDOMIZATION BETWEEN STRAIGHT FORWARD DRUGS LIKE HYDROXYCHLOROQUINE. THEN AT THE BOTTOM AS WE ADD ADD SECOND AND THIRD RANDOMIZATION THEY WERE INTRODUCED LATER IN THIS ADAPTIVE TRIAL DESIGN. THIS SHOWS YOU THE OVERALL PATENT OF RECRUITS. SO WE TRACK THE OUTBREAK IN THE UK. WE HAD A BIG FIRST WAVE, QUIET SUMMER, MODERATE SECOND, THIRD WAVE WITH EARLY RELEASE AND MASSIVE OUTBREAK HUGE NUMBER OF CASES IN JANUARY. HIT THE PEAK IN FIRST WAVE, 400 PATIENT AS DAY. WE LOOK CLOSE TO THAT BUT UN UNFORTUNATELY WE DID SO IN JANUARY MULTIPLE 500 PATIENTS PER DAY. YOU CAN SEE THE TOP RIGHT THERE ABOVE THE MAP OF THE UK WE HAVE CURRENTLY GOT 176 RECRUITING SITES AND YOU CAN SEE GBR IDN AND NPL WHICH JUST OPENED IN INDONESIA IN THE FALL SO WE HAVE SOME SITES TO TREAT PATIENTS THERE. YOU CAN SEE THOSE NUMBERS, THE PHASE 1, 2, 3, 4, 5, THAT'S THE DIFFERENT RANDOMIZATION PHASES, PHASE 1 IS THE STRAIGHT FORWARD DRUGS, HYDROXYCHLOROQUINE, ET CETERA. PHASE 2 IS THOSE LIZ HAS BEEN, PHASE 3 CONVALESCENT PLASMA, PHASE 4 IS ASPIRIN, PHASE 5 IS (INAUDIBLE). THIS IS JUST ABOUT TWO DAYS OLD. THAT SCREEN SHOT. IT IS A VERY -- TRIAL, OPEN TO ALL AGES SO OUR YOUNGEST PATIENT IS 1, OLDEST IS 103. SO INCLUSIVITY OF AGE BROKEN RECORD. OPEN TO PREGNANT WOMEN AND CHILDREN OBVIOUSLY. SO GOT ABOUT 200 CHILDREN, WE HAVE A SLIGHTLY DIFFERENT SUB PROTOCOL IN CHILDREN MOSTLY FOR THE MULTI-INFLAMMATORY SYNDROME. AND WE ARE ENROLLING PREGNANT WOMEN, WE HAVE A OBSTETRICS AND PREGNANT WOMEN SUBGROUP RUN BY OBSTETRICIANS. (INAUDIBLE) IT IS QUICK, IT IS EASY. THIS SHOWS YOU THE SYSTEM CAPTURES THE TIME TO RAP DOCUMENTIZE. YOU CAN -- RANDOMIZE. MEDIAN TIME TO RANDOM RANDOMIZE IS SIX MINUTES SO WE HAVE CAPTURED THAT PART AND HAD SUCCESS WITH APPROACHING LARGE NUMBERS OF PATIENTS. WE DESIGN THE EVOLVE ADAPTIVE TRIAL, THE FIRST RANDOMIZATION, IT WAS STARTED OFF WITH JUST ADULTS AND ADMITTED TO HOSPITAL WITH SARS COVE INFECTION ON RANDOMIZE IN 2 TO 1 TO 1 TO 1 TO 1 RADIO. TWO STANDARD OF CARE VERSUS EACH OF THESE ARMS, WITH THE OUTCOMES BEING PRIMARILY DEATH WITHIN 28 DAYS AND SECONDARY OUTCOMES DURING RATION OF HOSPITALIZATION OHIO -- DURING DURATION OF HOSPITALIZATION. WE QUICKLY CHANGED PROBE INFECTION TO PROBE SUSPECTED BECAUSE THERE WAS TOO MUCH DELAY EARLY ON GETTING PCR TESTS RESULTS TURNED AROUND. THAT IS WORKED OUT FINE IN TERMS MOST OF OUR ARMS, ABOUT 90% OF PATIENTS PCR POSITIVE AND AMONG THOSE NOT WHEN WE LOOK FOR EXAMPLE IN CONVALESCENT ARM MOST TRIALS ALSO HAVE SARS COV ANTIBODIES SO WE BELIEVE CERTAINLY 90% ARE SARS COVID 95% OR MOVE COVID INFECTION. SO WE START WITH THAT COSIGN, SOON AFTER WE ADDED A SECOND RANDOMIZATION. IT WAS BECOMING CLEAR INFLAMMATORY PROCESS AND MAYBE DRUGS HELP THERE SO WE INTRODUCED A SECOND RANDOMIZATION FOR PATIENTS WHO DETERIORATED WITH A DECLINING SATURATION AND INCREASING CRP THEY CAN BE ADDITIONALLY RANDOMIZED TO TOSILIZAMAB WITH SIX ADDITIONAL DOSES WITH TREATMENT. WHEN CONVALESCENT PLASMA BECAME AVAILABLE IN THE OUTBREAK ONCE IT STARTED BEING COLLECTED WE INTRODUCED IT AS A -- PART OF THE MAIN RANDOMIZATION YOU GET RANDOMIZED TO THE FIRST ROLE OF DRUGS OR STANDARD OF CARE AND AT THE SAME TIME YOU RANDOMIZE TO CONVALESCENT PLASMA OR NULL CONVALESCENT PLASMA. SO THAT'S THE FACTORAL DESIGN, BALANCE ACROSS THE GROUPS. RANDOMIZATION ACROSS THE TWO SETS OF DRUGS. THEN LATER ONCE WE NEGOTIATED ACCESS TO MONOCLONAL ANTIBODY WITH REGIONERON AND MONOCLONAL COCKTAIL WE GET CONVALESCENT PLASMA WITH REGIONRON O OR NO ANTIBODY THERAPY. THAT WAS THE MOST COMPLEX OF THE DESIGN GOT TO AND 75 SOMEWHAT BECAUSE DRUGS HAS BEEN DROPPED DOWN. TO IS DRUGS WE LOOK AT SO FAR, WE HAD TEN, HYDROXYCHLOROQUINE, CONVALESCENT PLASMA, MONOCLONAL, REGIONERON. DEATH MENTION ZONE, TOSILIZIMAB. CULTUREESNE BARI CIRCUMSTANCESTNIB, JAC INHIBITOR AN ASPIRIN. WHERE POSSIBLE WE ARE TRYING TO LOOK AT WIDELY AVAILABLE DRUGS THAT COULD BE TESTED WITH MODEST EFFECTS THAT COULD BE USED INTERNATIONALLY. SO RESULTS SHOW FAR, THIS IS RE REVIEW EARLY ON IN THE PANDEMIC LOOKING WHAT HAPPEN CURRENT TREATMENT GUIDELINES SAID. ON THE LEFT THERE, COUNTRIES WERE RECOMMENDING USE OF HIGH TO BE SHY COLOR QUINN, REMDESIVIR AND ROTONOVIR ON THE BASIS OF -- TO BE HONEST, ON THE RIGHT THIS SHOWS YOU WHAT WAS BEING RECOMMENDED IN THE USE OF CORTICAL STEROIDS, MOST COUNTRIES WERE NOT RECOMMENDING THEY WERE SAYING DON'T GIVE STEROIDS IN COVID-19 BECAUSE OF I THINK MANY OF YOU PROBABLY KNOW THE HISTORY OF THAT WORRIES ABOUT SIDE EFFECTS AND ROLE REPUTATION. SO I WON'T GO INTOE DETAIL ABOUT RESULTS OF MANY NEED TO BE AWARE BUT CERTAINLY THREE DRUGS WIDELY RECOMMENDED WIDELY USED, E DEMONSTRATED WORKING EFFECTIVE. SO FIRST LOPINAVIR AND HYDROXYCHLOROQUINE, IF ANYTHING IT WAS HARMFUL IN HOSPITALIZED PATIENT AND ASIDS THROW MYSIN, TO MY DISAPPOINTMENT SHOWED NOTHING AT ALL. YOU COULDN'T REALLY SEPARATE IT FROM OVERALL ANY SUB GROUPS AND NO EFFECT WHICH IS A BUSINESS SURPRISING CONSIDERING YOU THINK IT MIGHT BE AFFECT ON BACTERIAL SECONDARY INFECTIONS BUT ABSOLUTELY NOTHING THERE. TO SHOW YOU HOW THE FACTUAL DESIGN WORKS IN TERMS OF EVENING THINGS OUT, FOR EXAMPLE AZITHROMYCIN SUPPLEMENTARY TABLES. YOU CAN SEE HERE PEOPLE TREATED WITH AZITHROMYCIN OVER 90% GOT IT AND THERE WAS SOME CONTAMINATION USUAL CARE, BUT BECAUSE IT WAS IN THE SAME RANDOMIZATION YOU WEREN'T RANDOMIZED TO RAPINOVIR OR HYDROXY HYDROXYCHLOROQUINE, IF PURPOSE Z PACK EXCLUSIVE. SO CONVALESCENT PLASMA FACTOR RAIL RAN TOMMIZATION, THEY ARE EQUALLY DISTRIBUTED ACROSS THE TWO ARMS, SO YOU GETS EQUALITY OF THOSE OTHER FACTUAL RANDOMIZATIONS SO CANCELS ITS OUT SO SHOULDN'T AFFECT AZITHRO USUAL CARE COMPARISON. THEN YOU CAN SEE SOMETHING LIKE REMDESIVIR WHICH IS NOT PART OF THE TRIAL. BECAUSE OF THE LARGE RANDOMIZATION YOU GET EQUALITY OF THOSE DRUGS ACROSS THE TWO GROUPS SO WE TEND TO GET DESIGN MOST OF THE OTHER TREATMENTS ARE VERY WELL DISTRIBUTED EQUALLY ACROSS THE TWO ARMS EXCEPT -- WHICH ALLOWS YOU TO MAKE INFERENCES. DEXMETHAZONE WAS POSITIVE RESULTS WE RANDOMIZED 2000 VERSUS 4,000 CONTROLS. WHAT WE SAW WAS THAT OVERALL, THERE WAS REDUCTION IN RISK OF 28 DAY DEATH STATISTICALLY SIGNIFICANT. WHEN WE LACKED IN PRE-SPECIFIED SUBGROUP ANALYSIS THERE WAS HETEROGENEITY ON RANDOMIZATION SO THE SCORE TEST, STATISTICALLY DIFFERENT RESULTS AND WE SHOULDN'T BE COMBINING THEM, ACTUALLY THE RIGHT THING TO DO IS TO PRESENT THEM AS SEPARATE RESULTS. WHICH IS WHAT WE HAVE DONE HERE TO SHOW QUITE A REMARKABLE EFFECT IN THE AMAZING VENTILATED PATIENTS WITH ABOUT REDUCTION OF ABOUT A THIRD IN RISK OF MORTALITY. AND ABOUT A FIFTH IN THOSE IN OXYGEN, CERTAINLY NO BENEFIT, THERE'S NOT AN OXYGEN POTENTIALLY HARM. SO THAT'S WAS OUR FIRST POSITIVE FINDING AND WAS VERY GRATIFYING BECAUSE IT IS CHEAP AND WIDELY AVAILABLE DRUGMENT IT ALSO HAD OTHER BENEFITS, CONSISTENT ACROSS ALL THE SUB GROUPS AND IT WAS CONSISTENT WITH THE SECOND END POINTS, SO PATIENTS WITH DEXAMETHASONE WERE MORE LIKELY DISCHARGED ALIVE AND MORE LIKELY TO GET OFF VENTILATION AND LESS LIKELY TO HAVE DEATH SO CONSISTENT PANEL THIS DRUG IS BENEFICIAL. THIS SHOWS YOU THE CAP PLAN MIRE FOR SUCCESSFUL REMOVAL FROM VENTILATION, THOSE WITH DEXAMTHASONE. THE BENEFITS IN THAT PATIENT GROUP. SO PLEASED WITH THAT, IT SHOWED NUMBERS SAVING LIVE IN THE FACE OF VENTILATION WAS ABOUT EIGHT. SO QUITE SIGNIFICANT FINDING. THIS WAS SUBSEQUENTLY LOOKED AT IN THE META ANALYSIS THOUGH CRITICALLY ILL PATIENTS, THIS IS A SUBSET OF OUR DATA, THIS ANALYSIS, WE HAVE OTHER TRIALS WE CAN -- ON THIS, YOU CAN SEE HERE WHEN YOU PUT THEM TOGETHER, THE RECOVERY TRIAL IS THE BIGGEST SQUARE HERE ON THE RIGHT SHOWING MOST OF THE INFORMATION IS FROM THE RECOVERY TRIAL WHERE ALL STACKS UP IN LINE AND CONFIRMING THAT THERE IS A SIGNIFICANT BENEFIT OF STEROIDS NOT JUST COURT -- NOT JUST DEXAMETHASONE BUT OTHER STEROIDS IN PATIENTS WITH CRITICAL COVID. WITH A NUMBER OF ABOUT 11, SO CLOSE TO WHAT RESEARCH -- CONVALESCENT PLASMA, VERY QUICKLY. WE HAVE A NATIONAL BLOOD AND TRANSPLANT SERVICE SO THEY TEST ALL BLOOD TRANSFUSION, SO THEY DETECTED CONVALESCENT PLASMA, WE HAD A A RELEASE CRITERION OF EUROIMMUN SIGNAL CUT OFF OF GREATER AND THERE 6 TO MAKE SURE IT WAS HIGH TITER PLASMA. THE FDA DEFINED HIGH TITER USING VARIOUS ASSAYS BUT USING THIS ASSAY THAT I DID FIND GREATER OR EQUAL TO 3.5 SO PLASMA GREATER THAN EQUAL TO SIX. SO IT'S WHAT THE FDA CONFERRED HIGH TITER. WE TRIED TO GIVE TWO DOSES, FROM DIFFERENT DONORS AND INCREASE CHANCES OF PATIENT BEING HIGH TITER PLASMA. ABOUT A MONTH AGO THE DATA MONITORING COMMITTEE LOOKED AT BLINDED DATA ON THE TEN AND A HALF THOUSAND RANDOMIZED PATIENTS AND OF WHICH 1800 DEATHS AND THEY SAID THERE WAS NO -- THEY SAW THERE WAS NO SIGNIFICANT DIFFERENCE IN THE PRIMARY END POINT 28 DAY AND 18% DEATH IN CONVALESCENT PLASMA VERSUS 18% IN USUAL CARE ALONE. SO THEY RECOMMENDED TO THE OTHER CHIEF INVESTIGATOR TO CLOSE RECRUITMENT FOR FUTILITY. WE DID THAT AND RELEASED THE TOP LINE RESULT AND WE NOW AS OF TODAY HAVE PRETTY COMPETE FOLLOW-UP ON 11 AND A HALF THOUSAND PATIENTS RANDOMIZED TO CONVALESCENT PLASMA SO JUST IN THE PROCESS OF REVIEWING THE FINAL RESULTS, THEY SHOULD BE AVAILABLE SOON. SO HOPEFULLY WILL BE ABLE TO GET MORE INFORMATION ABOUT CONVALESCENT PLASMA HERE SOON. THEN THE MOST RECENT RESULT WAS THE TOSILIZAMAB RESULT RELEASED THURSDAY. THIS IS THE DATA BEFORE THE TOCILIZUMAB RESULT OUTCOME RECOVERY SO THERE'S SMALLISH TRIALS, INCONCLUSIVE, THE TWO TRIALS FROM THE MANUFACTURER HAD EQUIVOCAL FINDINGS, SOME BENEFITS IN REDUCE DURATION TO STAY IN THE HOSPITAL ICU AND BENEFITS IMPACT TO BENEFIT ON THE OUTCOME OF VENTILATION DEATH BUT NO BENEFIT ON OVERALL PRIMARY END POINT MORTALITY. THEN REMAP CAP, ICU TRIAL, IMPORTANT TO BENEFITS, HUGE AND TRIAL REPORTED A HARM, WE STOPPED EARLY. SO THE OVERALL LOOKING AT THE META ANALYSIS, ABOUT 9% REDUCTION IN RISK OF DEATH BUT NON-SIGNIFICANT SO STILL UNCERTAINTY AROUND BENEFIT TOCILIZUMAB. SO WE ENROLL PATIENTS INTO TOCILIZUMAB AS PART OF THE SECOND RANDOMIZATION SO THEY HAVE TO HOSPITALIZED, CLINICALLY OR SARS COV-2 INFECTION, HAD OXYGEN SATURATION LESS THAN 92%, ALL OXYGEN FACE MASK AND VENTILATION. AND THEY KNEAD TO CRP OF 75 OR MORE. EXCLUSION ARE PRETTY LIMITED, NO ACTIVE TB OR CLEAR EVIDENCE, NON-ACTIVE INFECTION. WE CLOSED ENROLLMENT 24 JANUARY BECAUSE WE RECEIVED SAMPLE SIZE, THAT'S NUMBER OF DOSES WE HAD AVAILABLE FOR THE TRIAL, THIS SHOWS YOU THE CHARACTERISTICS OF THE PATIENTS, A THIRD, 17, THIRD, OTHER. (INAUDIBLE) ABOUT 45% WERE ON SIMPLE OXYGEN ONLY, SO THIS IS A GROUP NOT STUDIED IN -- 40% ON NON-INVASIVE MECHANICAL VENTILATION, THREE TIMES NUMBER NEEDED IN THE STUDY IN THAT CATEGORY. AND 14% ON THE BAYESIAN -- WHICH IS TWICE (INAUDIBLE) MOST PATIENTS WERE ON CORTICOSTEROIDS. BECAUSE MOST PATIENTS WERE ENROLLED AFTER WE ANNOUNCED THE COURT CO-STEROID RESULT, THOSE (INAUDIBLE) ENROLLED. MOST OF TESTIFY -- ILL FOR ABOUT TEN DAYS IN THE HOSPITAL ABOUT TWO DAYS AND MANY WITH C REACTIVE PROTEIN WAS 143 WHICH IS LESS THAN WE -- BUT STILL HIGH. AND AS I SAID, CRITERIA IS 75% OR MORE. THIS WAS THE OVERALL RESULT WE SAW, IT WAS REDUCTION IN THE RISK OF MORTALITY DAY 28, ABOUT 14% STATISTICALLY SIGNIFICANT. SO WHAT THIS DID IF WE PUT THIS BACK INTO THE ME THE ANALYSIS, WHICH IS THE BOX ON THE BOTTOM YOU CAN SEE MOST OF THE DATA COMES FROM RECOVERY BUT IT LINES UP PRETTY MUCH WITH THE META ANALYSIS HAS SHOWN BEFORE, IT WAS PRETTY MUCH -- BRINGS IT NARROWS THE CONFIDENCE INTERVALS CONSIDERABLY AND MAKES IT STATISTICALLY SIGNIFICANT ABOUT 13% RISK REDUCTION WHICH IS SIGNIFICANT. YOU CAN SEE THE -- RESULT RECOVERY IS NOT INCONSISTENT WITH THE OTHER RESULTS JUST THE OTHER RESULTS WERE SMALLER TRIALS SO THERE IS MUCH MORE VARIABILITY IN THE DATA SO (INAUDIBLE). SO REALLY THINKING IF WE LOOK AT PRE-SPECIFIED SUB GROUPS, WHAT WE SAW WAS AN EFFECT -- RESULT THAT WAS CONSISTENT WITH THE BENEFITS ACROSS ALL THE PRESPECIFIED SUB GROUPS. SO CONSISTENT WITH AGE, GENDER,ETH MISTY, DAYS SYMPTOM ON SETS, YOU COULD LOOK AT THAT AND SAY THERE WERE TRENDS IN THERE BUT IF YOU LOOK AT THE SQUARES AND P VALUES THERE'S NO STATISTICAL EVIDENCE OF DIFFERENCE BETWEEN SUB GROUPS CONSISTENT WITH BENEFIT BEING SEEN IN SUB GROUPS. ALSO NO DIFFERENCE BY LEVEL OF SUPPORT. SO APPEAR THOSE WORKED WITH SIMPLE OXYGEN NON-INVASIVE MECHANICAL VENTILATION AND THOSE WITH MECHANICAL VENTILATION. INTERESTING THERE THAT WITH THE CORTICOSTEROIDS IS CLEARLY A BENEFIT ON TOP OF CORTICOSTEROIDS, BUT POTENTIALLY INTERACTION THERE WHERE BENEFIT IS NOT TAKING CORTICAL STEROIDS I WOULD URGE CAUTION THERE BECAUSE THE CAI SQUARE ISN'T HUGE AND THERE IS A TIME ISSUE, THE PATIENTS WHO ARE NOT ON STEROIDS WERE EARLY ON IN OUTBREAK AND THEN PRACTICED CHANGED AND EVERYONE WAS ON STEROIDS. SO IT COULD BE THIS WAS AN EARLY FLUCTUATION IN THE DATA THAT DIDN'T GET A CHANCE TO CORRECT ITSELF BECAUSE AFTER THE 16TH OF JUNE NOT ENROLLING ANY PATIENTS NOT ON STEROIDS SO YOU NEED TO BE CAUTIOUS ABOUT INTERPRETATION IN THAT. BUT ALSO ASSOCIATED WITH GETTING OUT OF HOSPITAL EARLIER SO THIS WAS THE PROBABILITY BEING 28 DAY WITH TOCILIZUMAB WAS STATISTICALLY BETTER GETTING OUT OF THE HOSPITAL IN 28 DAYS. WE SAW THAT EFFECT ACROSS SUB GROUPS. SO IF HE WERE ON NO -- SORRY I CAN'T SEE. SO THIS WAS THE END POINT MECHANICAL VENTILATION OR DEATH THOSE NOT ON MECHANICAL VENTILATION BASED ON ONE OF OUR SECONDARY END POINTS SO IT WAS BENEFICIAL IN BOTH THOSE ON SIMPLE OXYGEN AND THOSE ON NON-INVASIVE VENTILATION AND BENEFICIAL SUBSEQUENT TO DEATH OR MECHANICAL VENTILATION, SEEN ON TOP OF CORTICAL STEROIDS. WHAT WE DIDN'T SEE WAS AN EFFECT OF TOCILIZUMAB ON PROBABILITY OF GETTING OFF INVASIVE MECHANICAL VENTILATION IF YOU WERE ALREADY MECHANICICALLY VENTILATED. SO IF SUMMARY, TOCILIZUMAB WAS SUCCESSFUL AMONG PATIENTS HOSPITALIZED WITH COVID WITH HYPOXIA AMELIORATES CRP, REDUCED MORTALITY, INCREASE PROBABILITY OF HOSPITAL DISCHARGE. ALIVE 28 DAYS AND REDUCE PROBABILITY OF PROGRESSING TO INVASIVE MECHANICAL VENTILATION AND DEATH. WE SAW THAT BENEFIT ACROSS ALL THE PRE-SPECIFIED PATIENT SUB GROUPS AGE GENDER DURATION OF SYMPTOMS,ETH IN THIS AT THIS, AND THAT BENEFIT WAS IN ADDITION TO CORTICOSTEROIDS. THIS IS HOW THE TRIAL CURRENTLY LOOKS. WE HAVE CULTURESENE VERSUS USUAL CARE AS SIMPLE IMMUNE MODULATOR. WE ARE STILL STUDYING REGIONRON H VERSUS USUAL CARE, ASPIRIN VERSUS USUAL CARE, AND WE JUST ADDED BARASIZIMAB AS VERSUS USUAL CARE. THIS IS OUR CURRENT RECRUITMENT, REGIONRON VERSUS USUAL CARE IS 4,000 PATIENTS ON ACTIVE TREATMENT VERSUS 4,000 CONTROLS ROUGHLY. NATIONAL ACTUALLY IS 6,000 VERSUS USUAL CARE COLCHICINE IS 5,000 VERSUS 5,000 AND BARICITINB, INTRODUCED TEN DAYS AGO IS AT 550 VERSUS 550. SO THE REASON THOSE REGEN ASPIRIN ARE BIGGER THAN PREVIOUS TARGETS SAMPLE SIZE AROUND 2000, MAINLY REGENRON WITH OUR EXPERIENCE WITH CONVALESCENT PLASMA, WE WANT TO LOOK AT THE SUBGROUP VERSUS ANTIBODY NEGATIVE WHICH IS ABOUT 40% OF THE EMISSIONS SO WE NEED TO SCALE THE SAMPLE SIZE CORRECTLY. AND THE ASPIRIN AND COLCHICINE BECAUSE THEY ARE CHEAP AND WIDELY AVAILABLE WE WANT TO DETECT A SMALLER EFFECT SIZE SO IN THOSE WE ARE TARGETING THE -- BEING ABLE TO DETECT DOWN TO 12 1/2% REDUCTION IN MORTALITY GET UP TO ABOUT 14 1/2 THOUSAND PATIENTS TOTAL RANDOMIZATION. NEW DEVELOPMENT WE HAVE BEEN PLANNING TO DO RECOVERY WHICH IS PHASE 2 STUDY SO BRINGING PHASE 2 STUDIES SO WE ARE NOW DOING PHASE 2 STUDIES IN SUBSET OF PATIENTS AND SITES. AND WE JUST OPENED RECOVERY INTERNATIONAL SO WE ARE PLANNING TO OPEN -- NEPAL, THIS WEEK (INDISCERNIBLE). WHAT'S THE LEGACY? THERE'S QUITE A LOT OF TALK ABOUT THE CLINICAL TRIALS AND SUCCESS OF RECOVERY MODEL. I THINK REALLY WHAT WE WANT TO DO IS FOR LEGACY TO BE FOR CLINICAL RESEARCH TO BE INDEBTED IN ROUTINE CARE WE HAVE SHOWN YOU CAN DO ACROSS THE UK IN ABOUT TEN PERCENT OF THE HOSPITALIZED PATIENTS WHO RECRUITED TO RECOVERY MANY THE UK. AND IT'S DONE BY STAFF AT THE FRONT END, NOT BY HIGHLY SPECIALIZED RECEPTORS SO THIS IS A PHOTOGRAPH OF AN INTENSIVE CARE ADMISSION, SHOWING INTENSIVE CARE BEDS ARE FULL OF COVID PATIENTS AND YOU CAN SEE THAT IT'S BECOMING STANDARD, BASICALLY IF YOU ARE ADMITTED TO INTENSIVE CARE, COVID EACH TRIAL NEED TO BE ADMITTED TO TRIAL AND CHIEF MEDICAL OFFICER WAS CLEAR, NO OFF LABEL USE OF UNPROVEN THERAPEUTICS, YOU CAN'T STOP IT HAPPENING BUT IT WAS STRONGLY DISCOURAGED. YOU ONLY TRY THESE THINGS DO THEM IN A TRIAL, WOULD BE GOOD FOR YOU AND FOR THE CURRENT PATIENT AND FOR THE FUTURE PATIENTS. SO WE HOPE THAT WILL BE THE LEGACY. JUST TO FINISH, REALLY TO THANK EVERYONE, THIS IS A HUGE EFFORT, I'M SORT OF ONE OF THE TWO CHIEF INVESTIGATORS BUT THERE IS A HUGE TEAM WITH A VAST AMOUNT OF RESOURCES BEING THROWN ACROSS THE WHOLE OF THE NHS AND NATIONAL HEALTH RESEARCH INFRASTRUCTURE. SO EVERY HOSPITAL HAS HEALTH RESEARCH STAFF PAID TO NATIONAL PROGRAM. OF COURSE TO THE THOUSANDS AND THOUSANDS OF -- WHO PARTICIPATED AND THE PATIENTS AND FAMILIES WHO AGREED TO DO THE TRIAL. THANK YOU VERY MUCH, STEVE. I HOPE I DIDN'T OVERRUN. >> PROFESSOR HORBY, THANK YOU VERY MUCH FOR THIS REALLY ENLIGHTENING PRESENTATION. I WOULD JUST LIKE TO REMIND THE AUDIENCE THAT THE CODE NUMBER FOR CME TODAY IS 31844. THE MAGIC NUMBER ACCORDING TO DR. HOLLAND. SO THERE HAVE BEEN SOME QUESTIONS COMING THROUGH THE CHAT. SO I WOULD LIKE TO START BY ASKING YOU YOU SHOWED VERY NICELY THAT BROAD RANGE OF AGE RECRUITD IN RECOVERY. WHAT HAS BEEN THE RACIAL AND ETHNICITY DIVERSITY OF THE STUDY PARTICIPANTS? DOES IT REFLECT OVERALL THE UK POPULATION? >> IT'S PRETTY GOOD. THE EPIDEMIC HASN'T AFFECTED DIFFERENT PATIENT GROUPS OR ETHNIC GROUPS IN THE UK. IN THE SAME WAY. SO WHAT WE HAVE SEEN IS MORE INTENSE OUTBREAKS IN POORER PARTS OF THE COUNTRY, SOCIOECONOMIC DISEASE AS WELL. AND WE HAVE SEEN HIGHER ATTACK RATES IN RACIAL ETHNIC MINORITY GROUPS, WE RECRUITED 16, 17% OF THE RECRUITS ARE FROM ETHNIC MINORITY BACKGROUND WHICH IS FAIRLY REFLECTIVE IN THE UK, PERHAPS AS A BIT OF AN UNDERESTIMATE POST TOTAL PROPORTION OF ALL CASE IN THE UK. >> SO THE OTHER QUESTION THAT I HAVE, FROM THE AUDIENCE IS, WHETHER THERE IS ANY PLAN FOR OUTPATIENT OR NON-HOSPITALIZED PATIENT, ANY TREATMENT STUDIES PARTICULARLY NOW WITH THE ROLL OUT OF VACCINATION WHERE THERE MIGHT BE FEWER HOSPITALIZATIONS? >> SO WE HAVE CUP -- NATIONAL TRIALS. WHAT WE HAVE IS WE HAVE WHAT'S CALLED NATIONAL URGENT HEALTH PRIORITY TRIALS SO IN PUBLIC HOSPITALS IN THE UK. THERE IS NO RESOURCE PROVIDED FOR A TRIAL UNLESS ITs BEEN BADGED -- DOESN'T MEAN YOU CAN'T DO A TRIAL BUT MEANS YOU WON'T GET SUPPORT TO THE NATIONAL SYSTEMS. WHICH MEANT MOST OF THE RESEARCH IS STOPPED SO IN THE HOSPITAL SYSTEM THERE ARE TWO NATIONAL TRIALS, ONE IS RECOVERY, THE OTHER ONE IS -- INTERNATIONAL ICU TRIAL. THERE'S ALSO A OUTPATIENT STUDY CALLED PRINCE, A NATIONAL TRIAL STUDY DRUGS SEEING OUTPATIENTS SO IT'S STUDYING HIGH RISK PATIENTS WITH EARLY DISEASE TO TRY TO PREVENT PROGRESSION ADMISSION TO THE HOSPITAL. >> THE OTHER QUESTION THAT I HAVE, IS HOW DO YOU MONITOR THE SITES AND ASSURE DATA INTEGRITY SUBMITTED FROM THE SITES? IF THERE IS ANY INTEREST IN ADDING IN THE KVAALRY? >>PROFESSOR: WE ARE LUCKY BECAUSE OF THE NATIONAL INCAGE SO WE CAN CROSS CHECK EVERYTHING SO IF PEOPLE (INAUDIBLE) MECHANICAL VENTILATOR, YOU CAN CHECK THAT AGAINST AT LEAST TWO OTHER DATA SETS FROM HOSPITAL STATISTICS WHICH IS BASICALLY HOSPITAL ACCOUNTING SYSTEMS AND THE NATIONAL INTENSIVE CARE ALL THE DATABASE WHICH IS EVERY INTENSIVE CARE UNIT. ONE OF THE OUTCOMES, YES, WE GET -- WE ARE ABSOLUTELY SURE THAT WE HAVE THAT, ABSOLUTELY CORRECT. THERE ARE OTHER THINGS WHICH MAYBE LESS ACCURATE. FOR EXAMPLE, META PATIENTS GOT TREATMENT OR NOT, WE SHOULD BE ABLE TO LOOK AT THAT IN A BIT MORE DETAIL BUT GENERALLY WE HAVE MINIMUM ESTIMATES, 80 TO 90% COMPLIANCE WITH DRUG TREATMENT, PROBABLY HIGHER THAN THAT. BUT THAT IS -- >> OKAY. >> FIBERNECTIN. >> OF COURSE. >> SO WE HAVE -- WE USED TO GET FLOODED WITH EMAILS ABOUT PEOPLE SAYING TRY THIS, TRY THAT, TRY THE OTHER. IT WAS FLOODING OUR INBOX SO IT BECAME UNTENABLE TO MANAGE THAT SO THE UK SET UP A NATIONAL PRIORITIZATION SYSTEM SUCH AS NIH HAS WHERE WE HAVE INDEPENDENT SCIENTIFIC COMMITTEE THAT REVIEWS ALL THE APPLICATIONS UNDER DIFFERENT ANTI-VIRALS IMMUNE MODULATORS, ANGIOTENSIN SYSTEM, AND THEY REVIEW ALL THAT AND THEY GIVE US ADVICE AND RECOMMEND THINGS TO BE TRIOLET NEAR THE OUTPATIENT SETTING OR IN INPATIENT SETTING. WE CAN REFUSE -- WE ARE FREE TO REJECT THOSE RECOMMENDATIONS BUT GENERALLY WE DON'T. THOUGHT THERE WAS NO CASE, NO SCIENTIFIC CASE, THERE WAS NOVEMBER PLAUSIBLE MECHANISM AND THEY WERE UNDERCONVINCED BY BY THE STUDIES REPORTED SO FAR. >> SPECIFICALLY FOR THE VIRAL SIGNALING, ARE YOU DOING SOMETHING REGARDING THROMBO EPIBOTIC COMPLICATIONS OR THE POSSIBILITY THAT IT MAYBE AFFECTING THOSE? OR ARE YOU DOING SOMETHING SPECIAL AS FAR AS PREVENTION OF THROMBO EMBOLIC DISEASE? >> NO, WE ARE NOT, WE ARE COLLECTING DATA ON THROW BOW EMBOLIC PATIENTS, IN ALL THE ARMS. THE EXTENT IT IS A ISSUE IS HARD TO SAY. THERE'S META ANALYSIS THAT SUGGESTS IT IS IT IS NOT A BIG ISSUE. THE OTHER PATIENTS NOW ARE ON OUT OF THE ICU ON THERAPEUTIC ANTI-COAGULATION, IT WAS ON -- SO WE FELT THERE WAS NO NEED TO DO AN ADDITION. >> VERY INTERESTING QUESTION ABOUT THE REGENERON. ARE YOU COMBINING THAT WITH SEQUENCING AND HOW ARE YOU GOING TO SEE WHETHER THERE ARE VARIANTS THAT MAYBE AFFECTING THE RESULTS? >> WE ARE NOT DOING THAT. WE HAVE KEPT THE TRIAL AS SIMPLE AS POSSIBLE. WE ONLY -- THE ONLY BIOLOGICAL -- PEOPLE GET DIAGNOSTIC TESTS THROUGH THE NATIONAL SYSTEM AND LINK TO THE TEST BUT IT IS NOT ROUTINELY SEQUENCED SO SOME OF THE -- THERE IS AN UNBIASED SEQUENCE IN THE PROGRAM RANDOMLY SELECT PATIENTS TO SEQUENCE SO SOME WILL BE SEQUENCED BUT NOT ALL OF THEM. THE ONLY BIOLOGICAL TEST WE PUT IN PLACE WAS BASELINE ANTIBODY TESTS BECAUSE WE FELT IT WAS REALLY IMPORTANT TO START BY CONVALESCENT PLASMA AND REGENERON BY PRESENCE OR ABSENCE OF ANTIBODIES SO WE ARE NOT BUT THERE ARE DISCUSSIONS GOING ON ABOUT PUTTING IN PLACE A NATIONAL SYSTEM TO DO THAT IN IMMUNOCOMPROMISED PATIENTS WHO HAVE GIVEN MONOCLONALS OR CONVALESCENT PLASMA. >> GREAT. SO THERE ARE -- I'M GOING TO COMBINE A FEW QUESTIONS ABOUT REMDESIVIR. CLEARLY WAS NOT STUDIED AS A SEPARATE DRUG BUT IT LOOKS LIKE IT HAS BEEN USED SIGNIFICANTLY IN RECOVERY. SO GIVEN THE RESULTS OF THE REALITY TRIAL, THERE THE RESULTS OF -- SOME TRENDS IN MORTALITY BUT NOT DEFINITIVE DATA, HAVE YOU DONE OR ARE YOU PLANNING ON DOING ANY SEPARATE ANALYSIS ON THE REMDESIVIR USAGE IN RECOVERY AND ANALYZE ITS DATA EITHER IN THE CONTEXT OF THE TOCILIZUMAB STUDY OR OTHER ARMS? >> REMDESIVIR IS A LOT LESS POPULAR IN THE UK THAN ELSEWHERE. PEOPLE ARE NOT CONVINCED OF THE BENEFITS OF IT TO BE HONEST IN THE -- TRIALS SHOWING KNOW FATALITY BENEFIT IN THE TRIALS SAYING NO FATALITY BENEFIT AND SHORTENED PERIOD OF ADMISSION, LESS THAN THAT SHOWN IN SOME OF THE TOCILISUMAB STUDIES. I KNOW THERE IS A BIG FRENCH STUDY THAT JUST CLOSED, THAT MAY GIVE US MORE INSIGHT INTO THE REMDESIVIR. WE DO -- WE ARE SYSTEMATICALLY LOOK AT THE INTERACTIONS, WE HAVE FOR INSTANCE INTERACTION BETWEEN TOCILIZUMAB AND REMDESIVIR, REMDESIVIR DOESN'T MAKE A DIFFERENCE, EXACTLY THE SAME RESULT. SO WE HAVE NOT SEEN ANY INTERACTION. >> SO THE OTHER QUESTION IS REGARDING THE MORTALITY THAT SEEMED TO BE PRETTY HIGH IN THE TOCILISUMAB STUDY AND ALSO SOME OF THE PATIENTS WHO DIED, IN THE TOCILIZUMAB TRIAL DID NOT RECEIVE MECHANICAL VENTILATION SO IF YOU COULD PERHAPS ELABORATE ON THE HIGH MORTALITY RATES, I UNDERSTAND THESE WERE PATIENTS WHO WERE ALREADY ON OTHER MEDICATIONS, AND ALSO THE FACT THAT THERE WERE SOME DEATHS WITHOUT MECHANICAL VENTILATION. >> YEAH. SO WHAT YOU NOTICE IN ALL RECOVERY PUBLICATIONS DEATH RATE IS 20% PLUS. THAT BASICALLY IS EFFECTIVE OVER IN THE UK. THE IS ANOTHER MASH NATIONAL STUDY CLINICAL DATA ABOUT 30% OR MORE HOSPITAL ADMISSIONS, SO WE HAVE NATIONAL DATA AND FIRST WAVE ON AVERAGE 30% IN THE HOSPITAL MORTALITY. AND ANY -- SORRY. IN MORE RECENT TIMES IT'S COME DOWN BUT AROUND 20% SO IN THE WHOLE OF THE UK THE AVERAGE MORTALITY IN THE HOSPITAL IS 20%. SO WE RECRUIT ABOUT 10% HOSPITAL PATIENTS SO THE 20% IS EFFECT REFLECTIVE OF THE UK SITUATION. WHAT EXTENT THAT IS DUE TO DEMOGRAPHICS, IN OUTBREAKS HOSPITAL ADMISSION I DON'T KNOW BUT IT IS REFLECTIVE OF THE UK POSITION. THEN FOR THE TOCILISUMAB, ON TOP OF THAT YOU HAD TO BE HYPOXIC AND HAD TO HAVE A CRP, ME THAT PUTS YOU IN MORE SEVERE PATIENT. NOW SOME PATIENTS DON'T HAVE MECHANICAL VENTILATION BECAUSE THEIR TREATMENT DECISIONS ARE MADE ABOUT FRAIL ELDERLY PATIENTS AND IF YOU LOOK AT AT THE DEXAMETHASONE, AS YOU GO UP THE SCALE, IN RESPIRATORY SUPPORT THE AGE GOES DOWN SO AGE IS LOWER IN THOSE WITH MECHANICAL VENTILATION THAN THOSE ON SIMPLE OXYGEN BECAUSE THE EXPERIENCE IS THAT TREATMENT RELATED DON'T GET OFF VENTILATORS SO THEY ARE NOT PUT ON THEM. >> THAT EXPLAINS IT. SO THERE IS AN ETHICS COMMITTEE QUESTION WHICH ACTUALLY CAME TO MY MIND WHEN YOU WERE PRESENTING. IS THERE A SINGLE INFORMED CONSENT FOR THE ENTIRE PILE OR IS THERE A CONSENT FOR EACH INTERVENTION? AND IF IT'S ONLY A SINGLE CONSENT HOW DO YOU MANAGE TO CONVENE THE ETHICS COMMITTEES TO USE TWO PAGES FOR THE DIFFERENT DRUG INTERVENTIONS? >> ONE CONSENT FORM. >> ALL THE INTERVENTIONS. >> I THINK IT'S STILL JUST TWO PAGES, I HAVE TO CHECK, THAT MAY HAVE GONE SLIGHTLY OVER. WITH ADDITION OF REGENERON. BUT YEAH, IT'S -- WE KEEP IT SIMPLE. THERE IS A PATIENT -- TWO PAGE PATIENT INFORMATION LEAF LET, SO THAT'S WHERE MOST OF THE DATA INFORMATION ABOUT ALL DRUGS IS KEPT. WITH (INAUDIBLE) 20% STAFFED TRAINED IN THE -- AND ON THE CONSENT FORM IS INFORMATION SHEET IS ABOUT INFORMATION CONSENT FORM IS JUST ABOUT -- >> OKAY. SO THERE IS AN INFORMATION WITH ALL THE SIDE EFFECTS OF THE DIFFERENT TYPES OF MEDICATIONS, >> YEAH. THE RISK BENEFITS AND THE INFORMATION -- >> I SEE. I SEE. WE WOULD YOU LIKE TO COMMENT ON BETA INTERFERON AS POTENTIAL? >> IT SEEMS TO BE -- THERE'S BEEN A LOT OF -- WE HAVE BEEN PRECISELY NOT TREATING WITH INTERFERON WHICH IS UK DRUG AND YET U.S. TRIALS. INITIALLY WE WERE GOING TO PUT THEM IN BUT THE SUPPLY WE NEEDED TO DO A DEFINITIVE TRIAL AND COMPANY WE WERE WORKING WANTED TO DO THEIR OWN SMALL TRIAL, WHICH THEY DID. SUBSEQUENT TO THAT THE -- THEY CHOSE SOLIDARITY TRIAL, OUR ROUTES OF ADMINISTRATION. SHOWED NO BENEFIT, IT WAS THE ARM THAT SHOWED MOST FOR HARM IN HOSPITALIZED PATIENTS. AND I THINK WHAT WE ARE SEEING, MORE CONFIDENCE THAT IN THE STAGE PATIENT WE ARE SEEING IN THE HOSPITALS ACTUALLY IT'S IMMUNE MODULATION IS SOMETHING PROOF OF CONCEPT HAS WORKED. IF WE ARE GETTING THINGS LIKE BARICITNIB AS THE INTERFERON PATHWAY AND AT THE SAME TIME GIVE INTERFERON IS COUNTER INTUITIVE AND SEEMS TO ME THE -- IT MAY WORK, BUT IF IT WORKS IT'S MORE LIKELY TO WORK IN DISEASE THAN -- >> RIGHT. RIGHT. IT LOOK AT LIKE THERE MIGHT BE TWO DIFFERENT SETS OF INTERVENTIONS. SO OPERATIONALLY, THERE IS A QUESTION, WHAT ADVICE WOULD YOU HAVE IN DOING A RECOVERY LIKE TRIAL IN COUNTRIES LIKE THE U.S. THAT DID NOT HAVE A NATIONAL HEALTHCARE SYSTEM OR DATABASE? >> I DON'T KNOW THE U.S. HEALTHCARE SYSTEM WELL BUT YOU HAVE ORGANIZATIONS, OBSERVATION STUDIES AND HEALTHCARE ORGANIZATIONS AND I DON'T SEE WHY NATIONS HAVE SYSTEMS IN PLACE, WHAT YOU NEED IS A GOOD HOSPITALS THAT HAVE SIMILAR SYSTEM AND SOME CURRENT LEVERAGE TO SAY WE WANT YOU TO PARTICIPATE, PARTICIPATE IN THIS TRIAL, AS AN EXPECTATION. AND WE EXPECT YOU YOU TO PARTICIPATE IN DATA LINKAGE. SO I DON'T -- OBVIOUSLY IT WOULD BE POSSIBLE NATIONAL SCARE BUT LIKELY POSSIBILITY LARGER SCALE (INAUDIBLE) BUT I DON'T HAVE MUCH IN THE SYSTEMS. >> YEP. THERE IS -- WE HAVE SOME PEOPLE WHO ARE WORKING ON THE GUIDELINES HERE. ON THE NIH GUIDELINES SO THERE IS A QUESTION WHETHER YOU WILL HAVE DATA THAT ARE MORE SPECIFIC ON THE DOSE AND DURATION OF CORTICOSTEROIDS IN THE TOCILIZIMAB TRIAL SO THEY CAN BE ANALYZED BASED ON EXPOSURE THEY HAD ON DEXAMETHASONE. >> NO THEY WOULDN'T HAVE THAT. >> OKAY. LET ME SEE. HAVE YOU IDENTIFIED ANY BIASES THAT MAYBE SIGNIFICANTLY INTERPRETATION OF YOUR RESULT? AS FAR AS SELECTION BIAS, FOR THE TRIAL -- I GUESS FROM THE WORK YOU SHOWED IT LOOKS LIKE THERE IS A PRETTY UNIVERSAL ACCEPTANCE OF THE TRIAL AND BUT DO YOU THINK THERE MIGHT BE SOME SELECTION BIAS AS FAR AS WHO IS MOVING FORWARD WITH PARTICIPATING? >> IF YOU LOOK AT THE WITH RESPECT TO PATIENTS ADMITTED, 10% OF ALL PATIENTS IN THE UK, IF YOU COMPARE THE CHARACTERISTICS, LOOKS VERY SIMILAR. AND THEN BECAUSE OF THE SCALE OF IT, RANDOMIZATION, MESHES OUT TO EVERYTHING ELSE. I REMEMBER GIVING A TALK HOW WELL YOU DIDN'T MEASURE THE SCORE, HOW CAN YOU -- BUT IF YOU LOOK AT THE BIGGEST PREDICTOR OF RISK OF DEATH IS AGE. AND THE BIGGEST DIFFERENCE WE HAVE HAD IN AGE IN ANY OF THE ARMS BECAUSE OF THE LARGE RANDOMIZATION WAS ONE AND A HALF YEARS. AND IF YOU CORRECT FOR THAT IT MADE NO DIFFERENCE SO THE CHANCES OF ANY OTHER UNRELATED COMPOUNDERS OF SCALE ACTING AND YOUR -- YOU RANDOMIZING VERY LARGE SCALE. >> SO THERE IS ANOTHER QUESTION THAT HAS TO DO WITH LONG TERM FOLLOW-UP. IS THERE ANY LONG TERM FOLLOW-UP OF THESE PATIENTS TO SEE FOR EXAMPLE TO SEE LONG TERM OUTCOMES IN THE DIFFERENT ARMS OF THE TRIAL? >> SO WE HAVE DATA LINKAGE UP TO TEN YEARS AND WE CAN PRIMARY CARE RECORDS REHOSPITALIZATION, DEATH, REASON FOR REHOSPITALIZATION. SO YES, WE'RE GOING TO DO ALL THE ARMS WE HAVE SIX MONTHS MORTALITY AND FOR ALL T OF THE ARMS WE HAVE DATA LINKAGE UP TO TEN YEARS SO A HUGE AMOUNT WE CAN DO. THERE ARE ALSO OTHER SPECIFIC STUDIES LOOKING AT FOR EXAMPLE, NON-COVID SYMPTOMS AND DOING DATA LINKAGE IN THOSE STUDIES SO IT WOULD BE OTHER GROUPS WHO WILL BE FOLLOWING UP FOR EXAMPLE WITH LUNG FUNCTION TESTS IN SUBSET OF OUR PATIENTS, SEVERAL MECHANISMS, QUITE A LOT OF DATA. >> HOW COULD RECOVERY MOTIVATE AND SUSTAIN SITES TO ENROLL AT ACCELERATED PACE? >> WHAT'S SEEN AS A NATIONAL EFFORT. AND THEY HAVE SEEN SUCCESS, SO TO SAY A PATIENT ASKING WHOA I SHOULD I BE IN THIS TRIAL AND HE SAID I'M JUST PRESCRIBE YOU DEXAMETHASONE, IF IT WASN'T FOR THE TRIAL SO YOU CAN HAVE THE NEXT PATIENT. >> VERY GOOD POINT. WHAT WAS THE BUDGET OF RECOVERY PER ARM, DO YOU HAVE A BALLPARK OR IS THIS SOMETHING TO COMMENT ON? >> HARD TO SAY. BECAUSE THERE IS SUPPORT THROUGH -- WE DON'T PAY DOCTORS AT ALL, THEY DON'T GET ANYTHING. THEY ARE NATIONALLY EMPLOYED DOCTORS, IT'S SEEN AS PART OF ROUTINE CARE NOW TO NULL PATIENTS IN RESEARCH. THE RECENT RESEARCH COSTS PAID THROUGH NATIONAL SYSTEM THAT IS NOT HUGE, THE ORIGINAL GRANTS WAS 2 1/2 MILLION POUNDS. AND SO IT'S ABOUT 250 POUNDS PER PATIENT. >> PROFESSOR HORBY, YOU HAVE BEEN MOST GENEROUS WITH YOUR TIME. I THINK WE WILL WRAP IT UP. BEFORE WE CLOSE, DO YOU THINK THAT YOUR STUDIES AND HISTORY OF MEDICINE HAVE PREPARED YOU FOR THIS? >> PREPARED ME FOR ALL OF THE COLLATERAL NOISE OF PEOPLE SUGGESTING QUACKERY. PEOPLE SUGGESTING THIS IS ALL A CONSPIRACY. I THINK YOU CAN GO RIGHT BACK TO THE DAYS OF THE PLAGUE TO SEE EXACTLY THE SAME SOCIAL FIERCE IN VIRUSES PLAYING OUT. AND WE ARE NOT ESPECIALLY TARGETED, IT HAPPENS WITH EVERY EMERGENCY WITH A DANGEROUS -- >> WELL, THANK YOU, AGAIN. AND THANK YOU FOR ALL YOUR HARD WORK AND THANK YOU FOR TAKING ON THIS EFFORT AND HELPING US FIGHT THE PANDEMIC. THANK YOU. >> THANK YOU. THANKS FOR HAVING ME.