key: cord-0780645-t7kjh9yr authors: Khan, Fasihul; Fabbri, Laura; Stewart, Iain; Robinson, Karen; Smyth, Alan R; Jenkins, Gisli title: A systematic review of Anakinra, Tocilizumab, Sarilumab and Siltuximab for coronavirus-related infections date: 2020-04-26 journal: nan DOI: 10.1101/2020.04.23.20076612 sha: cfa1c9fbbacd1b653794c54a6adce6b18c7fc18f doc_id: 780645 cord_uid: t7kjh9yr Background There is accumulating evidence for an overly activated immune response characterised by the release of pro-inflammatory cytokines in severe Covid-19. Suppression of the inflammatory response with immunomodulatory therapies may be a potential therapeutic strategy. We systematically review and assess the effectiveness of specific interleukin-1 and -6 inhibitors for the treatment of coronavirus-related infections. Methods Electronic databases, pre-print servers and clinical trial registries were searched to identify current and ongoing studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of Covid-19 and other coronavirus related super infections. The co-primary outcome was time to hospital discharge (days) and severity on an ordinal scale measured at day 15. Results Five retrospective studies (tocilizumab, two case series and two case reports; siltuximab, one case series) were shortlisted for inclusion, totalling 59 patients. All studies had a moderate or high risk of bias, with multiple limitations. Insufficient data and inter-study heterogeneity prevented meta-analysis. Primary outcomes were inconsistently reported but suggest many patients experienced an improvement in status seven days following therapy. The case fatality ratio (CFR) of patients with severe Covid-19 included in our review was 6.8%, a figure substantially lower than that estimated in non-interventional case series. Of the studies measuring IL-6, all reported elevated baseline levels. Twenty-five ongoing registered clinical trials exploring immunomodulatory agents in Covid-19 were identified, although inconsistency in participants and endpoints are noted. Conclusion Inhibition of IL-6 with tocilizumab and siltuximab requires further evaluation in managing the assumed hyperinflammatory response associated with severe Covid-19. These early data are considered hypothesis generating and justify the need for well-designed randomised clinical studies. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. p o t e n t i a l t h e r a p e u t i c s t r a t e g y [ 5 ] . e a r s t o s h a r e a n u m b e r o f g e n e t i c a n d c l i n i c a l s i m i l a r i t i e s w i t h o t h e r z o o n o t i c c o r o n a v i r u s e s , i n c l u d i n g s e v e r e a c u t e r e s p i r a t o r y s y n d r o m e c o r o n a v i r u s ( S A R S ) a n d M i d d l e E a s t r e s p i r a t o r y s y n d r o m e ( M E R S ) [ 6 , 7 ] . T h e r e a r e a l s o r e p o r t s o f e l e v a t e d p r o i n f l a m m a t o r y c y t o k i n e s i n p a t i e n t s w i t h S A R S a n d M E R S [ 8 , 9 ] , s u g g e s t i n g o v e r l a p p i n g t h e r a p e u t i c t a r g e t s i n t h e m a n a g e m e n t o f S A R S , M E R S a n d C o v i d -1 9 . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2020. T h r o u g h s y s t e m a t i c r e v i e w a n d c r i t i c a l a p p r a i s a l o f t h e l i t e r a t u r e , w e a s s e s s t h e e f f e c t i v e n e s s a n d s a f e t y o f s p e c i f i c I L -1 ( a n a k i n r a ) a n d I L -6 ( t o c i l i z u m a b , s i l t u x i m a b , s a r i l u m a b ) i n h i b i t o r s f o r t h e t r e a t m e n t o f C o v i d -1 9 , w h i l s t c o n c u r r e n t l y d r a w i n g o n l i t e r a t u r e f r o m p r e v i o u s s i m i l a r c o r o n a v i r u s -r e l a t e d s u p e r -i n f e c t i o n s ( S A R S a n d M E R S ) . T h e s e a g e n t s a l r e a d y c a r r y a p p r o v a l f o r t h e t r e a t m e n t o f o t h e r r a r e n o n -i n f e c t i o u s a n T h e s y s t e m a t i c r e v i e w w a s c o n d u c t e d i n a c c o r d a n c e w i t h a p r e -s p e c i f i e d p r o t o c o l ( P R O S P E R O r e g i s t r a t i o n n u m b e r : C R D 4 2 0 2 0 1 7 6 3 7 5 ) , a n d h a s b e e n r e p o r t e d i n a c c o r d a n c e w i t h P R I S M A ( P r e f e r r e d R e p o r t i n g I t e m s f o r S y s t e m a t i c R e v i e w s a n d M e t a -A n a l y s e s ) g u i d e l i n e s [ 1 0 ] . S e a r c h s t r a t e g y a n d s t u d y s e l e c t i o n E l e c t r o n i c d a t a b a s e s e a r c h e s w e r e c a r r i e d o u t i n M E D L I N E ( 1 9 4 6 t o l a t e s t ) a n d E M B A S E ( 1 9 7 4 t o l a t e s t ) , a n d o n g o i n g c l i n i c a l t r i a l r e g i s t r i e s ( c l i n i c a l t r i a l s . g o v , E U C l i n i c a l T r i a l s R e g i s t e r a n d t h e C h i n e s e C l i n i c a l T r i a l R e g i s t r y ) , w i t h t h e l a s t s e a r c h c a r r i e d o u t o n 8 t h A p r i l 2 0 2 0 . D u e t o t h e e x p e c t e d s m a l l n u m b e r o f r e s u l t s , s e a r c h t e r m s w e r e k e p t b r o a d , a n d i n c l u d e d k e y w o r d s a n d c o n t r o l l e d v o c a b u l a r y f o r p a t i e n t a n d t r e a t m e n t -r e l a t e d t e r m s ( s e e a p p e n d i x f o r M E D L I N E s e a r c h s t r a t e g y ) . U n p u b l i s h e d a n d o n g o i n g s t u d i e s w e r e i d e n t i f i e d b y s e a r c h i n g p r e -p r i n t s e r v e r s i n c l u d i n g m e d R x i v , b i o R x i v , C h i n a X i v . S e a r c h e s w e r e c a r r i e d o u t i n d e p e n d e n t l y b y t w o r e v i e w e r s i n a s t a n d a r d i s e d m a n n e r w h i c h i n v o l v e d s c r e e n i n g b y t i t l e s . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2020. a n d a b s t r a c t s , f o l l o w e d b y f u l l t e x t r e v i e w . D i s a g r e e m e n t s w e r e r e s o l v e d b y c o n s e n s u s , w i t h u n r e s o l v e d c o n f l i c t s d e c i d e d b y a t h i r d r e v i e w e r . T h e r e v i e w i n c l u d e d a l l o r i g i n a l s t u d i e s i n c l u d i n g c o n f e r e n c e a b s t r a c t s a n d c a s e r e p o r t s , e v a l u a t i n g t h e u s e o f a t l e a s t o n e o f a n a k i n r a , t o c i l i z u m a b , s a r i l u m a b o r s i l t u x i m a b i v a s i v e m e c h a n i c a l v e n t i l a t i o n o r e x t r a c o r p o r e a l m e m b r a n e o x y g e n a t i o n ( E C M O ) ; i i i ) h o s p i t a l i s e d o n n o n -i n v a s i v e m e c h a n i c a l v e n t i l a t i o n o r h i g h f l o w o x y g e n d e v i c e s ; i v ) h o s p i t a l i s e d , r e q u i r i n g s u p p l e m e n t a l o x y g e n ; v ) h o s p i t a l i s e d , n o t r e q u i r i n g s u p p l e m e n t a l o x y g e n ; v i ) n o t h o s p i t a l i s e d . S e c o n d a r y o u t c o m e s i n c l u d e d t i m e t o c l i n i c a l i m p r o v e m e n t ( d a y s ) , d u r a t i o n o f m e c h a n i c a l v e n t i l a t i o n ( d a y s ) , o v e r a l l m o r t a l i t y , m o r t a l i t y a t 2 8 d a y s , t r e a t m e n t r e l a t e d a d v e r s e e v e n t s , I L -6 l e v e l s ( f o r r e v i e w s o f I L -6 i n h i b i t o r s ) . D a t a e x t r a c t i o n a n d r i s k o f b i a s a s s e s s m e n t D a t a w e r e e x t r a c t e d f r o m a r t i c l e t e x t a n d f i g u r e s u s i n g a p r e -d e f i n e d p r o f o r m a a n d v e r i f i e d b y a s e c o n d r e v i e w e r . I n f o r m a t i o n s o u g h t i n c l u d e d s t u d y d e s i g n a n d r e c r u i t m e n t s t r a t e g y , s a m p l e s i z e , p a r t i c i p a n t d e m o g r a p h i c s ( a g e , g e n d e r , s m o k i n g s t a t u s , c o m o r b i d i t i e s ) , c l i n i c a l i n v e s t i g a t i o n f i n d i n g s , i n t e r v e n t i o n c h a r a c t e r i s t i c s ( n a m e o f a g e n t , d o s e , r o u t e ) , t r e a t m e n t . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2020. r e l a t e d a d v e r s e e v e n t s , r e q u i r e m e n t a n d d u r a t i o n o f i n v a s i v e a n d n o n -i n v a s i v e v e n t i l a t i o n , u s e a n d d o s a g e o f o x y g e n , d u r a t i o n o f i n t e n s i v e c a r e u n i t ( I C U ) a n d h o s p i t a l s t a y , s u r v i v a l o u t c o m e m e a s u r e s a n d f o l l o w u p d u r a t i o n . T h e p r e -s p e c i f i e d s i x -p o i n t o r d i n a l p r i m a r y o u t c o m e s c a l e w a s s u b s e q u e n t l y a d a p t e d t o a f o u r -p o i n t o r d i n a l s c a l e a s o u t c o m e d e t a i l w a s i n c o n s i s t e n t , i ) d e a t h ; i i ) r e q u i r e m e n t f o r a r t i f i c i a l v e n t i l a t o r y s u p p o r t ( N I V / C P A P / I M V ) ; . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. . p o r t e d , t h e r e w a s a s t a t i s t i c a l l y s i g n i f i c a n t i m p r o v e m e n t i n o x y g e n s a t u r a t i o n s b y d a y f i v e p o s t -t r e a t m e n t . 1 5 p a t i e n t s ( 7 9 % ) h a d r e d u c e d o x y g e n s u p p o r t ; o n e n o l o n g e r n e e d e . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. ] . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. Q u a n t i t a t i v e s y n t h e s i s d e m o n s t r a t e s t h a t I L -6 w a s e l e v a t e d p r i o r t o i n t e r v e n t i o n w i t h t o c i l i z u m a b , a n d m e d i a n d i f f e r e n c e s e v e n d a y s l a t e r d e m o n s t r a t e d a f u r t h e r i n c r e a s e ( T a b l e 4 ) . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. T h r e e o n g o i n g c l i n i c a l t r i a l s o f s i l t u x i m a b i n C o v i d -1 9 w e r e i d e n t i f i e d w i t h a c o l l e c t i v e t a r g e t s a m p l e s i z e o f 4 9 2 p a r t i c i p a n t s o n c e c o m p l e t e ( T a b l e 6 ) . T h e f i r s t i s a n I t a l i a n s i n g l e -c e n t r e r e t r o s p e c t i v e s e r i e s o f 5 0 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. e x p e r i m e n t a l d r u g c a n b e i m p o s s i b l e [ 4 0 ] . N o s u i t a b l e s t u d i e s i n S A R S o r M E R S , o r s t u d i e s i n v e s t i g a t i n g s a r i l u m a b o r a n a k i n r a i n C o v i d -1 9 w e r e f o u n d . T w e n t y -f i v e r e g i s t e r e d c l i n i c a . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. T h e c a s e f a t a l i t y r a t i o ( C F R ) i n p a t i e n t s w i t h c r i t i c a l C o v i d -1 9 i s e s t i m a t e d t o b e a r o u n d 4 9 % , a l t h o u g h r e c o r d e d m o r t a l i t y r a t e s v a r y a c r o s s c o u n t r i e is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. i n t e r v e n t i o n c r i t e r i a w i t h s e v e r a l d i v e r s e e n d p o i n t s b e i n g s t u d i e d . T h i s m a y m a k e f u t u r e c o m p a r i s o n s a n d p o o l i n g o f r e s u l t s a c r o s s c l i n i c a l t r i a l s d i f f i c u l . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. t h e r a p y c a n b e r e c o m m e n d e d f o r c l i n i c a l u s e . O n g o i n g a n d f u t u r e t r i a l s , s u c h a s t h o s e s u m m a r i s e d h e r e , s h o u l d e n s u r e b a s e l i n e a n d f o l l o w u p d a t a i s c o m p l e t e f o r a l l p r i m a r y a n . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. E f f i c a c y a n d S a f e t y o f T o c i l i z u m a b i n t h e T r e a t m e n t o f S A R S -C o v -2 R e l a t e d P n e u m o n i a . h t t p s : / / C l i n i c a l T r i a l s . g o v / s h o w / N C T 0 4 3 3 2 9 1 3 . 2 1 . C h e c k p o i n t B l o c k a d e i n C O V I D -1 9 P a n d e m i c . h t t p s : / / C l i n i c a l T r i a l s . g o v / s h o w / N C T 0 4 3 3 5 3 0 5 . 2 2 . T o c i l i z u m a b i n t h e T r e a t m e n t o f C o r o n a v i r u s I n d u c e d D i s e a s e ( C O V I D -1 9 ) . h t t p s : . h t t p s : . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. C h a r a c t e r i s t i c s o f a n d I m p o r t a n t L e s s o n s F r o m t h e C o r o n a v i r u s D i s e a s e 2 0 1 9 ( C O V I D -1 9 ) O u t b r e a k i n C h i n a : S u m m a r y o f a R e p o r t o f 7 2 = 3 1 4 C a s e s F r o m t h e C h i n e s e C e n t e r f o r D i s e a s e C o n t r o l a n d P r e v e n t i o n . J a m a , 2 0 2 0 . 4 3 . I C N A R C r e p o r t o n C O V I D -1 9 i n c r i t i c a l c a r e -1 0 t h A p r i l 2 0 2 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. . https://doi.org/10.1101/2020.04.23.20076612 doi: medRxiv preprint T o c i l i z u m a b , w i t h s t a n d a r d d e v i a t i o n i n B . S m a l l c i r c l e s r e p r e s e n t i n d i v i d u a l d a t a p o i n t s w i t h i n c a s e s e r i e s f o r p e o p l e w h o s h o w e d c l i n i c a l s t a b i l i t y o r i m p r o v e m e n t , s m a l l c r o s s e s r e p r e s e n t i n d i v i d u a l d a t a p o i n t s w i t h i n c a s e s e r i e s f o r p e o p l e w h o c l i n i c a l l y d e t e r i o r a t e d o r d i e d , l a r g e c i r c l e s a r e i n d i v i d u a l d a t a p o i n t s f r o m c a s e s t u d i e s . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2020. . It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint S t u d y S t a t u s C o u n t r y D e s i g n S a m p l e s i z e P a r t i c i p a n t s I n t e r v e n t i o n C o m p a r a t o r P r i m a r y o u t c o m e N C T 0 4 3 3 0 6 3 8 R e c r u i t i n g B e l g i u m M u l t i -c e n t r e R C T 3 4 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint Middle East Respiratory Syndrome Coronavirus