Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

doi:10.1212/WNL.0000000000007242

. 2019 Apr 2;92(14):e1610-e1623.

doi: 10.1212/WNL.0000000000007242. Epub 2019 Mar 8.

Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

Leonard H van den Berg¹, Eric Sorenson², Gary Gronseth², Eric A Macklin², Jinsy Andrews², Robert H Baloh², Michael Benatar², James D Berry², Adriano Chio², Philippe Corcia², Angela Genge², Amelie K Gubitz², Catherine Lomen-Hoerth², Christopher J McDermott², Erik P Pioro², Jeffrey Rosenfeld², Vincenzo Silani², Martin R Turner², Markus Weber², Benjamin Rix Brooks², Robert G Miller², Hiroshi Mitsumoto²; Airlie House ALS Clinical Trials Guidelines Group

Affiliations

¹ From the Department of Neurology (L.H.v.d.B.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (E.S.), Mayo Clinic, Rochester, MN; Department of Neurology (G.G.), University of Kansas Medical Center, Kansas City; Department of Medicine (E.A.M.), Massachusetts General Hospital, Biostatistics Center, Harvard Medical School, Boston; Department of Neurology (J.A., H.M.), Columbia University, Eleanor and Lou Gehrig ALS Center, New York, NY; Department of Neurology (R.H.B.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (M.B.), University of Miami, FL; Neurological Clinical Research Institute (J.D.B.), Massachusetts General Hospital, Boston; Rita Levi Montalcini Department of Neuroscience (A.C.), University of Torino, Italy; Centre Constitutif SLA (P.C.), Université de Tours, France; Department of Neurology (A.G.), Clinical Research Unit, Montreal Neurological Institute, Neurosurgery, McGill University, Montreal, Canada; National Institute of Neurological Disorders and Stroke (A.K.G.), National Institutes of Health, Bethesda, MD; ALS Center (C.L.-H.), University of California San Francisco; Department of Neuroscience (C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK; Department of Neurology (E.P.P.), Section of ALS & Related Disorders, Cleveland Clinic, OH; Department of Neurology (J.R.), The Center for Restorative Neurology, Loma Linda University School of Medicine, CA; Department of Neurology and Laboratory of Neuroscience (V.S.), Istituto Auxologico Italiano, IRCCS, Milan; Department of Pathophysiology and Transplantation (V.S.), "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford, UK; Neuromuscular Diseases Unit/ALS Clinic (M.W.), Kantonsspital St. Gallen, Switzerland; Carolinas Neuromuscular/ALS-MDA Care Center (B.R.B.), Charlotte; Department of Neurology (B.R.B.), Carolinas Medical Center, University of North Carolina School of Medicine, Charlotte; Forbes Norris ALS Treatment and Research Center (R.G.M.), California Pacific Medical Center San Francisco; and Department of Neurosciences (R.G.M.), Stanford University, CA. L.H.vandenBerg@umcutrecht.nl.
² From the Department of Neurology (L.H.v.d.B.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (E.S.), Mayo Clinic, Rochester, MN; Department of Neurology (G.G.), University of Kansas Medical Center, Kansas City; Department of Medicine (E.A.M.), Massachusetts General Hospital, Biostatistics Center, Harvard Medical School, Boston; Department of Neurology (J.A., H.M.), Columbia University, Eleanor and Lou Gehrig ALS Center, New York, NY; Department of Neurology (R.H.B.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (M.B.), University of Miami, FL; Neurological Clinical Research Institute (J.D.B.), Massachusetts General Hospital, Boston; Rita Levi Montalcini Department of Neuroscience (A.C.), University of Torino, Italy; Centre Constitutif SLA (P.C.), Université de Tours, France; Department of Neurology (A.G.), Clinical Research Unit, Montreal Neurological Institute, Neurosurgery, McGill University, Montreal, Canada; National Institute of Neurological Disorders and Stroke (A.K.G.), National Institutes of Health, Bethesda, MD; ALS Center (C.L.-H.), University of California San Francisco; Department of Neuroscience (C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK; Department of Neurology (E.P.P.), Section of ALS & Related Disorders, Cleveland Clinic, OH; Department of Neurology (J.R.), The Center for Restorative Neurology, Loma Linda University School of Medicine, CA; Department of Neurology and Laboratory of Neuroscience (V.S.), Istituto Auxologico Italiano, IRCCS, Milan; Department of Pathophysiology and Transplantation (V.S.), "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford, UK; Neuromuscular Diseases Unit/ALS Clinic (M.W.), Kantonsspital St. Gallen, Switzerland; Carolinas Neuromuscular/ALS-MDA Care Center (B.R.B.), Charlotte; Department of Neurology (B.R.B.), Carolinas Medical Center, University of North Carolina School of Medicine, Charlotte; Forbes Norris ALS Treatment and Research Center (R.G.M.), California Pacific Medical Center San Francisco; and Department of Neurosciences (R.G.M.), Stanford University, CA.

PMID: 30850440
PMCID: PMC6448453
DOI: 10.1212/WNL.0000000000007242

Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

Leonard H van den Berg et al. Neurology. 2019.

. 2019 Apr 2;92(14):e1610-e1623.

doi: 10.1212/WNL.0000000000007242. Epub 2019 Mar 8.

Authors

Affiliations

¹ From the Department of Neurology (L.H.v.d.B.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (E.S.), Mayo Clinic, Rochester, MN; Department of Neurology (G.G.), University of Kansas Medical Center, Kansas City; Department of Medicine (E.A.M.), Massachusetts General Hospital, Biostatistics Center, Harvard Medical School, Boston; Department of Neurology (J.A., H.M.), Columbia University, Eleanor and Lou Gehrig ALS Center, New York, NY; Department of Neurology (R.H.B.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (M.B.), University of Miami, FL; Neurological Clinical Research Institute (J.D.B.), Massachusetts General Hospital, Boston; Rita Levi Montalcini Department of Neuroscience (A.C.), University of Torino, Italy; Centre Constitutif SLA (P.C.), Université de Tours, France; Department of Neurology (A.G.), Clinical Research Unit, Montreal Neurological Institute, Neurosurgery, McGill University, Montreal, Canada; National Institute of Neurological Disorders and Stroke (A.K.G.), National Institutes of Health, Bethesda, MD; ALS Center (C.L.-H.), University of California San Francisco; Department of Neuroscience (C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK; Department of Neurology (E.P.P.), Section of ALS & Related Disorders, Cleveland Clinic, OH; Department of Neurology (J.R.), The Center for Restorative Neurology, Loma Linda University School of Medicine, CA; Department of Neurology and Laboratory of Neuroscience (V.S.), Istituto Auxologico Italiano, IRCCS, Milan; Department of Pathophysiology and Transplantation (V.S.), "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford, UK; Neuromuscular Diseases Unit/ALS Clinic (M.W.), Kantonsspital St. Gallen, Switzerland; Carolinas Neuromuscular/ALS-MDA Care Center (B.R.B.), Charlotte; Department of Neurology (B.R.B.), Carolinas Medical Center, University of North Carolina School of Medicine, Charlotte; Forbes Norris ALS Treatment and Research Center (R.G.M.), California Pacific Medical Center San Francisco; and Department of Neurosciences (R.G.M.), Stanford University, CA. L.H.vandenBerg@umcutrecht.nl.
² From the Department of Neurology (L.H.v.d.B.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Department of Neurology (E.S.), Mayo Clinic, Rochester, MN; Department of Neurology (G.G.), University of Kansas Medical Center, Kansas City; Department of Medicine (E.A.M.), Massachusetts General Hospital, Biostatistics Center, Harvard Medical School, Boston; Department of Neurology (J.A., H.M.), Columbia University, Eleanor and Lou Gehrig ALS Center, New York, NY; Department of Neurology (R.H.B.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (M.B.), University of Miami, FL; Neurological Clinical Research Institute (J.D.B.), Massachusetts General Hospital, Boston; Rita Levi Montalcini Department of Neuroscience (A.C.), University of Torino, Italy; Centre Constitutif SLA (P.C.), Université de Tours, France; Department of Neurology (A.G.), Clinical Research Unit, Montreal Neurological Institute, Neurosurgery, McGill University, Montreal, Canada; National Institute of Neurological Disorders and Stroke (A.K.G.), National Institutes of Health, Bethesda, MD; ALS Center (C.L.-H.), University of California San Francisco; Department of Neuroscience (C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK; Department of Neurology (E.P.P.), Section of ALS & Related Disorders, Cleveland Clinic, OH; Department of Neurology (J.R.), The Center for Restorative Neurology, Loma Linda University School of Medicine, CA; Department of Neurology and Laboratory of Neuroscience (V.S.), Istituto Auxologico Italiano, IRCCS, Milan; Department of Pathophysiology and Transplantation (V.S.), "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford, UK; Neuromuscular Diseases Unit/ALS Clinic (M.W.), Kantonsspital St. Gallen, Switzerland; Carolinas Neuromuscular/ALS-MDA Care Center (B.R.B.), Charlotte; Department of Neurology (B.R.B.), Carolinas Medical Center, University of North Carolina School of Medicine, Charlotte; Forbes Norris ALS Treatment and Research Center (R.G.M.), California Pacific Medical Center San Francisco; and Department of Neurosciences (R.G.M.), Stanford University, CA.

PMID: 30850440
PMCID: PMC6448453
DOI: 10.1212/WNL.0000000000007242

Abstract

Objective: To revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS).

Methods: A consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry, and regulatory agencies) addressed 9 areas of need within ALS research: (1) preclinical studies; (2) biological and phenotypic heterogeneity; (3) outcome measures; (4) disease-modifying and symptomatic interventions; (5) recruitment and retention; (6) biomarkers; (7) clinical trial phases; (8) beyond traditional trial designs; and (9) statistical considerations. Assigned to 1 of 8 sections, committee members generated a draft set of guidelines based on a "background" of developing a (pre)clinical question and a "rationale" outlining the evidence and expert opinion. Following a 2-day, face-to-face workshop at the Airlie House Conference Center, a modified Delphi process was used to develop draft consensus research guidelines, which were subsequently reviewed and modified based on comments from the public. Statistical experts drafted a separate document of statistical considerations (section 9).

Results: In this report, we summarize 112 guidelines and their associated backgrounds and rationales. The full list of guidelines, the statistical considerations, and a glossary of terms can be found in data available from Dryad (appendices e-3-e-5, doi.org/10.5061/dryad.32q9q5d). The authors prioritized 15 guidelines with the greatest potential to improve ALS clinical research.

Conclusion: The revised Airlie House ALS Clinical Trials Consensus Guidelines should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS.

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References

1. Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology Committee on Research. J Neurol Sci 1999;169:2–12. - PubMed
1. Mitsumoto H, Brooks BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 2014;13:1127–1138. - PubMed
1. Writing Group; Edaravone (MCI-186) ALS Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017;16:505–512. - PubMed
1. de Boer AS, Eggan K. A perspective on stem cell modeling of amyotrophic lateral sclerosis. Cell Cycle 2015;14:3679–3688. - PMC - PubMed
1. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014;345:1247125. - PubMed

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[1] Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology Committee on Research. J Neurol Sci 1999;169:2–12. - PubMed

[2] Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology Committee on Research. J Neurol Sci 1999;169:2–12. - PubMed

[3] Mitsumoto H, Brooks BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 2014;13:1127–1138. - PubMed

[4] Mitsumoto H, Brooks BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 2014;13:1127–1138. - PubMed

[5] Writing Group; Edaravone (MCI-186) ALS Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017;16:505–512. - PubMed

[6] Writing Group; Edaravone (MCI-186) ALS Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017;16:505–512. - PubMed

[7] de Boer AS, Eggan K. A perspective on stem cell modeling of amyotrophic lateral sclerosis. Cell Cycle 2015;14:3679–3688. - PMC - PubMed

[8] de Boer AS, Eggan K. A perspective on stem cell modeling of amyotrophic lateral sclerosis. Cell Cycle 2015;14:3679–3688. - PMC - PubMed

[9] Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014;345:1247125. - PubMed

[10] Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014;345:1247125. - PubMed

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Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

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Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

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