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Clinical Studies….? Clinical research in the midst of an Ebola outbreak Peter Horby Brisbane, 1-2 June 2015 Acknowledgements Stephen Kennedy (PIRE, Liberia) Foday Sahr (DoD, Sierra Leone) Mohamed Samai (COMAHS, Sierra Leone) Jake Dunning, Trudie Lang, Jen Groves, Mandy Rojek, Gail Carson and many others at Oxford Annick Antierens and others at MSF Fiona Gannon and others at GOAL Tim Brooks (Public Health England) John Whitehead (Lancaster, Trial Statistician) Chimerix Inc. / Tekmira Pharmaceuticals Inc. The RAPIDE trial teams The ISARIC, PREPARE and The Global Health Network Teams in Oxford The MSF and MoH teams in country The Ebola Patients Sponsor: University of Oxford Funder: Wellcome Trust Background The therapies The trials The challenges Lessons learned & next steps 13th August 2014 “investigators have a moral duty to evaluate these interventions in the best possible clinical studies that can be conducted under the circumstances of the epidemic.” The therapies Promising candidates Product What is it? Evidence ZMapp Ebola antibody cocktail Solid protection in monkeys TKM-Ebola RNA inhibitor Solid protection in monkeys Brincidofovir Small molecule with Antiviral activity in broad antiviral activity cell lines Favipiravir RNA polymerase Solid protection in inhibitor mice. Antiviral in monkeys Convalescent Antibodies from Failed in monkeys plasma recovered patients Repurposed therapies Product – Primary Comment Azithromycin (Zithromax) Widely used in critically ill pts Sertraline (Zoloft) Large safety db – healthy pts Chloroquine Large safety db – healthy pts Amiodarone (Cordorone) Clinical data in Ebola pts Erlotinib / Sunitinib Combination rx with phase 3 data Product - Secondary Comment Cepharanthine “Anti-inflammatory” licensed in Japan Interferon products Systemic reactogenicity Toremifene (Fareston) Black box warning - hypokalemia 9 TKM-Ebola The Favipiravir trials Convalescent plasma ZMapp Brincidofovir Rapid Assessment of Potential RAPIDE Interventions & Drugs for Ebola RAPIDE Objective Rapidly assess and triage a number of potential Ebola treatments in Phase 2 studies. Survival Conclusion Outcome (a) 80% Very effective Maximize benefits (b) 67% Promising Justification for RCT (c) 50% Ineffective Minimize wasted effort RAPIDE trial design Cooper B et al. PLoS Med. 2015 Apr 14;12(4):e1001815. Probabilities of reaching each conclusion for the phase II trial of treatment Exact probabilities for Phase 2 with 140 cases p = true probability of surviving for 14 days p description Probability of reaching conclusion: (a) (b) (c) 0.800 very effective 0.908 0.092 0.000 0.667 promising 0.034 0.950 0.016 0.500 ineffective 0.000 0.100 0.900 Maximum sample size = 140 24 straight successes (a) 12 straight failures (c) Rapid Assessment of Potential RAPIDE Interventions & Drugs for Ebola Brincidofovir trial Scientific Title Open-label, non-randomised single arm trial to investigate the efficacy of Brincidofovir compared to historic controls or Ebolavirus Disease in an outbreak setting in West Africa Clinical Phase 2 Trial Design Open-label, non-randomised, single arm trial Trial Participants Patients with confirmed Ebolavirus disease attending the participating treatment centre Planned Sample Size Up to 140 adult participants, paediatric enrolment according to presentation over the same recruitment period Investigational Brincidofovir (BCV) Medicinal Product Formulation, Dose, Patients ≥50 kg: 200 mg initial dose, then 100 mg twice weekly Route of for 4 doses Administration Patients <50 kg: 4mg/kg initial dose, then 2 mg/kg twice weekly for 4 doses Treatment duration 2 weeks Follow up duration 30 days follow-up Objectives Outcome Measures Primary To evaluate the impact of Mortality at Day 14 BCV treatment on early mortality in EVD Secondary 1. To evaluate the impact of 1. BCV treatment of adults and a) Time to meeting EVD treatment children on: center discharge criteria. b) Mortality at Day 30 after first dose a) Time to recovery of study treatment b) Late mortality c) Day 4 viral load c) Viral load d) Presence and duration of d) EVD symptoms symptoms (Days 1-14) e) EVD antibody response e) Convalescent anti-Ebolavirus IgG titer (Day 30) 2. To assess the safety of BCV 2. Incidence of SARs and key adverse treatment of adults and events (Days 1-14) children Rapid Assessment of Potential RAPIDE Interventions & Drugs for Ebola TKM-Ebola-Guinea Trial Tekmira’s Lipid Nanoparticle Platform Components: Amino Lipid Structural Lipid PEG - Lipid Nucleic Acid 40-140 nm diameter Jeffs et al. Pharm. Res. 2005. siRNA Proof-of-Concept non-Human Primates Geisbert et al, Lancet 2010; 375: 1896-905 20 Ebolavirus Zaire Outbreak in Guinea, March 2014 Guinea Variant Is Divergent From Kikwit, Original Target of TKM-100802 siRNA + 99 Sierra Leone sequence entries Jun-Jul 2014 Phylogenetic analysis suggests single clade distinct from outbreaks in central Africa Baize et al, NEJM Apr 16 2014 Product details: TKM-130803 • siRNA cocktail adjusted to Guinea strain • Wet formulation • IV once daily infusion over two hours • Seven days treatment • 100 treatment courses Simple, pragmatic trials . Consecutive enrollment & analysis . Dead or alive on day 14 . Max 100-140 patients . What could possibly go wrong? ★ ★ ★ ★ Challenges to research: PEARLS POLITICAL ETHICAL ADMIN REGULATORY LOGISTICAL SOCIETAL PEARLS - Political PEARLS - Ethical so long as standard requirements for human research ethics are met, all scientifically recognized methodologies and study designs should be considered as ethically acceptable— whether they are placebo controlled randomized trials or trials that don’t involve randomization to choosing the trial design that will control groups. both answer the question at issue and also be ethically and practically acceptable to the community in Pregnancy / children which the research is to be conducted. PEARLS - Administrative Grant awarded DM system Protocol Drug Selected Contracts Ethics -- Oxford Ethics - Liberia Import license Export drug Final agreements First Patient 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 Sept Oct Nov Dec Jan PEARLS - Regulatory This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues, clients or customers visit http://www.djreprints.com. http://www.wsj.com/articles/chimerix-scraps-testing-of-experimental-ebola-drug-in-liberia-1422739087 BUSINESS Chimerix Scraps Testing of Experimental Ebola Drug in Liberia Declining Ebola Infection Rat e Contributed to Company’s Decision By PETER LOFTUS Jan. 31, 2015 4:18 p .m. ET Chim er ix I nc. scr apped t est ing of it s exper im ent al ant ivir al in Ebola pat ient s in Liber ia, saying t he num ber of infect ions had dr opped in r ecent w eeks, and t hat only a handful of pat ient s had been enr olled in t he Liber ian s t udy. The abr upt r ever sal in Chimerix ’s plans could r aise questions about whet her t he declining number of Ebola infections in W est Afr ica could be a pr oblem for o t her exper im ent al dr ugs and vaccines cur r ent ly under g oing t est ing in t he r egion for safet y and efficacy. The Wor ld H ealt h Or ganizat ion said t his w eek t he incidence of t he deadly disease cont inues t o fall in t he t hr ee count r ies t hat w er e har dest hit last year —Guinea, Liber ia and Sier r a Leone. M or e t han 22,000 people had been infect ed wit h Ebola and m or e t han 8 ,800 had died as of Jan. 25, pr im ar ily in t he t hr ee W est African countries, accor ding t o WH O. Chim er ix, of Dur ham , N.C., said in a news r elease issued lat e Fr iday t hat aft er discussions wit h t he U.S. Food and Dr ug Adm inist r at ion, t he com pan y “ is ceasing further participation in all current and future clinical s tudies of brincidofovir ” for Ebola vir us disease. This includes a st udy in Liber ia sponsor ed b y t he U.K.’s Univer sit y of Oxfor d, which began in J anuar y. Pet er H or by, an Oxfor d r esear cher who w as helping t o r un t he st udy, said t he decision t o halt it “ ar ose fr om bilat er al discussions bet ween Chim er ix and t he FD A.” H e said he wasn’t awar e of any r easons for t he decision beyond declining case num ber s. An FDA r epr esent at ive couldn’t im m ediat ely be r eached. The com pany said t he num ber of new cases of conf ir m ed Ebola vir us disease in Liber ia “ has decr eased signif icant ly, wit h only a handful of pat ient s enr olled t o dat e” in t he PEARLS - Logistical Ebola, AIDS Manufactur ed by Western Pharmaceuticals, US D oD? | The Liber ian Obser ver 08/12/2014 09:31 E-EDITION LOGIN ADVERTISING ARCHIVES SEARCH Calling all citizen journalists: If it has happened, is happening or is about to happen in your community, let us know. Find our contact info at the bottom of this page. For the latest, follow us on Facebook at https://www.facebook.com/pages/Liberian-Observer- It is 9:30 am in Monrovia on Monday, December 08, 2014 Online/42279623238 HOME NEWS BUSINESS OPINION SPORTS COLUMNS LIB LIFE WEIRD NEWS OBITUARIES HOME / NEWS / SECURITY / EBOLA, AIDS MANUFACTURED BY WESTERN PHARMACEUTICALS, US DOD? Safari Power Saver Click to Start Flash Plug-in Weather Forecast | Weather Maps Liber ian Obser v er E-Edition Subscribe to our full PDF version for access to job vacancies, ads, requests for proposals, invitations to bid, legal notices, obituaries and more! Scientists allege deadly diseases such as Ebola and AIDS are bio weapons being tested on Africans.
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