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      Efficacy and safety of givosiran for acute hepatic porphyria: 24‐month interim analysis of the randomized phase 3 ENVISION study


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          Background & Aims

          Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria.


          Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.


          Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period.


          Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.


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          A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity.

          Regression methods were used to select and score 12 items from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to reproduce the Physical Component Summary and Mental Component Summary scales in the general US population (n=2,333). The resulting 12-item short-form (SF-12) achieved multiple R squares of 0.911 and 0.918 in predictions of the SF-36 Physical Component Summary and SF-36 Mental Component Summary scores, respectively. Scoring algorithms from the general population used to score 12-item versions of the two components (Physical Components Summary and Mental Component Summary) achieved R squares of 0.905 with the SF-36 Physical Component Summary and 0.938 with SF-36 Mental Component Summary when cross-validated in the Medical Outcomes Study. Test-retest (2-week)correlations of 0.89 and 0.76 were observed for the 12-item Physical Component Summary and the 12-item Mental Component Summary, respectively, in the general US population (n=232). Twenty cross-sectional and longitudinal tests of empirical validity previously published for the 36-item short-form scales and summary measures were replicated for the 12-item Physical Component Summary and the 12-item Mental Component Summary, including comparisons between patient groups known to differ or to change in terms of the presence and seriousness of physical and mental conditions, acute symptoms, age and aging, self-reported 1-year changes in health, and recovery for depression. In 14 validity tests involving physical criteria, relative validity estimates for the 12-item Physical Component Summary ranged from 0.43 to 0.93 (median=0.67) in comparison with the best 36-item short-form scale. Relative validity estimates for the 12-item Mental Component Summary in 6 tests involving mental criteria ranged from 0.60 to 107 (median=0.97) in relation to the best 36-item short-form scale. Average scores for the 2 summary measures, and those for most scales in the 8-scale profile based on the 12-item short-form, closely mirrored those for the 36-item short-form, although standard errors were nearly always larger for the 12-item short-form.
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            A 12-Item Short-Form Health Survey

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              The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory.

              Fatigue is a major disease and treatment burden for cancer patients. Several scales have been created to measure fatigue, but many are long and difficult for very ill patients to complete, or they are not easy to translate for non-English speaking patients. The Brief Fatigue Inventory was developed for the rapid assessment of fatigue severity for use in both clinical screening and clinical trials. The study enrolled 305 consecutive, consenting adult inpatients and outpatients with cancer who could understand and complete the self-report measures used in the study. The same instruments also were administered to 290 community-dwelling adults to obtain a comparison sample. Research staff completed a form that indicated the primary site and stage of the cancer, rated the Eastern Cooperative Oncology Group performance status of the patient, described the characteristics of the pain, and described the current pain treatment being provided to the patients. The BFI was shown to be an internally stable (reliable) measure that tapped a single dimension, best interpreted as severity of fatigue. It correlated highly with similar fatigue measures. Greater than 98% of patients were able to complete it. A range of scores defining severe fatigue was identified. The BFI is a reliable instrument that allows for the rapid assessment of fatigue level in cancer patients and identifies those patients with severe fatigue.

                Author and article information

                Liver Int
                Liver Int
                Liver International
                John Wiley and Sons Inc. (Hoboken )
                16 November 2021
                January 2022
                : 42
                : 1 ( doiID: 10.1111/liv.v42.1 )
                : 161-172
                [ 1 ] Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit University of Modena and Reggio Emilia Modena Italy
                [ 2 ] Section on Gastroenterology and Hepatology Wake Forest University/North Carolina Baptist Medical Center Winston‐Salem NC USA
                [ 3 ] Centre Français des Porphyries Paris France
                [ 4 ] Hospital Clinic Barcelona Barcelona Spain
                [ 5 ] UCSF Liver Center and Porphyria Center, University of California San Francisco CA USA
                [ 6 ] King’s College Hospital London UK
                [ 7 ] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai New York NY USA
                [ 8 ] University of Texas Medical Branch Galveston TX USA
                [ 9 ] University of Utah Salt Lake City UT USA
                [ 10 ] Center for Hematology Massachusetts General Hospital Boston MA USA
                [ 11 ] Instituto Nacional de Pediatría Mexico City Mexico
                [ 12 ] Konkuk University Medical Center Seoul South Korea
                [ 13 ] University of Alberta Hospital Edmonton Canada
                [ 14 ] Alnylam Pharmaceuticals Cambridge MA USA
                [ 15 ] Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital Stockholm Sweden
                Author notes
                [*] [* ] Correspondence

                Paolo Ventura, MD, Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy.

                Email: paoloven@ 123456unimore.it

                Author information
                © 2021 The Authors. Liver International published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 31 August 2021
                : 21 October 2021
                Page count
                Figures: 3, Tables: 2, Pages: 12, Words: 7666
                Funded by: Alnylam Pharmaceuticals , doi 10.13039/100006400;
                Original Article
                Genetics and Rare Liver Diseases
                Custom metadata
                January 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:20.07.2022

                Gastroenterology & Hepatology
                acute hepatic porphyria,ala synthase‐1,givosiran,health‐related quality of life,rnai therapeutics


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