Title {1}	Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments
Trial registration {2a and 2b}.	ClinicalTrials.gov, NCT03116126. Registration 14 April 2017 EudraCT: 2016-002598-36
Protocol version {3}	15 Jun 2016 v1.0 – Original 26 Aug 2016 v.1.1 – Amendment stating the stratification of patients into mild and moderate AD 16 May 2017 v1.2 – Amendment minor changes and corrections to protocol following TSC (Trial Steering Committee) meeting to clarify statements 26 Sep 2018 v1.3 – Amendment minor changes updating contact information and references 19 Mar 2020 v1.4 – Amendment to include special COVID measures addressing March 2020 COVID-related research suspension 08 Jun 2020 v1.5 – Amendment to resume trial activities post-COVID research suspension. The addition of the ADCS-CGIC and audio recording of cognitive assessments.
Funding {4}	Active drug and placebo for the trial are provided through by an Investigator-Initiated Research grant (IIR-GBR-000792) from Takeda (formerly Shire) Pharmaceuticals and the trial is funded by the UK National Institute for Health Research (NIHR) through the Research for Patient Benefit (RfPB) Programme (Grant reference: PB-PG-0214-33098). The design, management, analysis and reporting of the study are independent of manufacturer of the drug and placebo. The views expressed are those of the author(s) and not necessarily those of the NIHR or Department of Health and Social Care. Additional support for the trial has been provided by Imperial College Healthcare NHS Trust and the NIHR Biomedical Research Centre at Imperial College London.
Author details {5a}	Karen Hoang 1,2, Hilary Watt 3, Mara Golemme 4, Richard J. Perry 1,2, Craig Ritchie 5, Danielle Wilson 4, James Pickett, Chris Fox 6, Robert Howard 7, Paresh A. Malhotra 1,2,4 1. Department of Brain Sciences, Imperial College London, United Kingdom 2. Imperial College Healthcare NHS Trust, London, United Kingdom 3. Department of Public Health and Primary Care, Imperial College London, United Kingdom 4. UK Dementia Research Institute Care Research and Technology Centre, Imperial College London and the University of Surrey, United Kingdom 5. Edinburgh Dementia Prevention and Centre for Clinical Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom 6. Norwich Medical School, University of East Anglia, Norfolk, United Kingdom 7. Division of Psychiatry, University College London, Maple House 149 Tottenham Court Road, London W1T 7NF, United Kingdom PAM conceived the study. PAM, RJP, CR, DW, JP, CF and RH initiated the study design and KH and MG with implementation. PAM is the grant holder. HW provided statistical expertise in the clinical trial design and is conducting the primary statistical analysis. All authors contributed to the refinement of the study protocol and approved the final manuscript.
Name and contact information for the trial sponsor {5b}	Trial Sponsor: Imperial College London Sponsor’s Reference: 16IC3372 Contact name: Research Governance and Integrity Team (RGIT) Address: Imperial College Healthcare NHS Trust, Norfolk Palace Road, London, W1 2PG Telephone: 02033110204 Email: rgit.ctimp.team@imperial.ac.uk
Role of sponsor {5c}	The sponsor and funding source had no role in the design of this study and will not have any role during its execution, analysis, interpretation of the data or decision to submit results.