HDClarity: a Multi-site Cerebrospinal Fluid Collection Initiative to Facilitate Therapeutic Development for Huntington's Disease
Conditions: Huntington's Disease
Sponsor: University College, London

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
Page 1 of 38 
Clinical Study Protocol 
 
HDClarity: a multi-site cerebrospinal fluid collection initiative 
to facilitate therapeutic development for Huntington's disease 
PROTOCOL NO.: 
UCL-CHDI-1 
CHIEF INVESTIGATOR: 
Edward Wild, MA MB BChir PhD MRCP 
UCL Institute of Neurology 
Box 104 
National Hospital for Neurology & 
Neurosurgery 
Queen Square, London 
WC1N 3BG, UK 
 
Phone: + 44 203 108 7489 
Fax: 
+ 44 207 611 0129 
e.wild@ucl.ac.uk 
SPONSOR: 
University College London 
Gower Street, London 
FUNDING SOURCE: 
CHDI Foundation, Inc. 
c/o CHDI Management, Inc. 
155 Village Boulevard 
Suite 200 
Princeton, NJ 08540 
Phone: + 1 609 945 9600 
Fax: 
+ 1 609 452 2160 
PROTOCOL DATE AND VERSION: 
 27 October 2021 (Version No. 004.1)  
© 2014-15 UCL / CHDI Foundation, Inc. 
Except where otherwise noted, this document is licensed under a 
Creative Commons Attribution 4.0 International License.   
 
 

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
Page 2 of 38 
 
 
PROTOCOL  APPROVAL SIGNATURES 
 
 
 
This Clinical Study Protocol is approved by: 
 
27 October 2021 
Signature: ……………………………………………… 
Date: …………………….. 
Edward Wild, MA MB BChir PhD MRCP 
Chief Investigator 
 
 
27 October 2021 
Signature: ……………………………………………… 
Date: …………………….. 
Cristina Sampaio, MD, PhD 
Chief Clinical Officer 
CHDI Management, Inc. 
 
 
 

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
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CHANGE LOG 
Date 
Description of change(s) 
Name 
2016-06-21 Addition of UK sites and update to CHDI study personnel  
Elena Pak 
 
2018-12-19 
Compliance with EU General Data Protection Regulation (GDPR); 
removal of recruitment cap at 600 participants; change to 
huntingtin gene cytosine-adenine-guanine (CAG) expansion 
exclusion criteria for participant with manifest disease; relaxation 
of blood test exclusion criteria for minor abnormalities of no 
clinical significance; seeking permission to contact participants 
about future enrollment; addition of South American sites; and 
minor clarifications and corrections 
Ed Wild 
2021-10-27 
Revising repeated annual enrollments into a longitudinal open-
ended study design, with re-consent every 4 years; Annual 
Screening Visits at regular intervals after the first Annual 
Screening Visit (i.e. at 1, 2, 3 years and so on) ± 2 months; 
Optional Repeat Sampling Visits during the first year of 
enrollment only; addition of two new participant cohorts for 
juvenile manifest HD, and HD participants with a huntingtin gene 
cytosine-adenine-guanine (CAG) of 36-39 repeats; and minimum 
age for controls and participants with premanifest disease reduced 
from 21 to 18 years. Urine pregnancy test has been added to each 
screening and sampling visit for females of child bearing potential. 
Lumbar puncture can be performed any time of day after a fast of 
at least 6 hours, or overnight.  
Ed Wild 
 
 

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
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Site Principal Investigator Signature Page 
Protocol Number: 
UCL-CHDI-1 
Protocol Title: 
HDClarity: a multi-site cerebrospinal fluid collection 
initiative to facilitate therapeutic development for 
Huntington's disease 
Protocol Date and Version: 
27 October 2021, Version No. 004 
Funding Source: 
CHDI Foundation, Inc. (CHDI) 
c/o CHDI Management, Inc. 
155 Village Boulevard 
Suite 200 
Princeton, NJ 08540 
Phone: +1 609 945 9600 
By my signature below, I hereby attest that I have read and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
I am aware of my responsibilities as an investigator under the guidelines for Good Clinical 
Practice (GCP), local regulations (as applicable), the Declaration of Helsinki, and the study 
protocol. I agree to conduct the study according to these guidelines and to appropriately direct 
and assist the staff under my control, who will be involved in the study. 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB)/Ethics Review Board (ERB). I understand that any changes in the 
protocol must be approved in writing by CHDI and the IRB/ERB before they can be 
implemented, except where necessary to eliminate hazards to participants. 
 
 
 
 
 
Site Principal Investigator's Signature 
 
Date 
 
 
 
 
 
 
Site Principal Investigator Name (Print) 
 
 
 

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
Page 5 of 38 
 
Synopsis 
Name of the Funding Source: 
CHDI Foundation, Inc.  
Protocol No.: UCL-CHDI-1 
Study Title: HDClarity: a multi-site cerebrospinal fluid collection initiative to facilitate 
therapeutic development for Huntington's disease 
Short Study Title: HDClarity 
Planned Study Sites: Multiple sites in Europe, North America, South America, and 
Australasia. 
Number of Participants planned: participants across 8 clinical cohorts will be 
enrolled at multiple sites up to an estimated minimum of 2500 participants or until 
the study is terminated by either the Funding Source or Sponsor  
Chief Investigator: 
Professor Edward Wild 
MRC Clinician Scientist, UCL Institute of Neurology; 
Honorary Consultant Neurologist, National Hospital for Neurology & Neurosurgery, 
Queen Square 
London WC1N 3BG, UK 
Study period: Ongoing from August 1, 2016 
Date first participant enrolled: January 24, 2017 
Estimated date last participant completed: the study is open to continuous 
recruitment up to an estimated minimum of 2500 participants 
Objectives: 
Primary: The primary objective of this study is to generate a high quality 
cerebrospinal fluid (CSF) sample collection for evaluation of biomarkers and 
pathways that will enable the development of novel treatments for Huntington's 
disease (HD). 
Secondary: 
• To generate a high quality plasma sample collection matching the CSF collections, 
which will also be used to evaluate biomarkers and pathways of relevance to HD 
research and development. 
• To collect phenotypic and clinical data for each participant. 
Study Design: 
This is a longitudinal open-ended observational study. Participants will attend two 
annual study visits, an Annual Screening Visit followed by an Annual Sampling Visit, 
and may also attend an optional visit during the first year of enrollment, an Optional 
Repeat Sampling Visit. 
During the Annual Screening Visit, medical history, and clinical and phenotypic data 
will be obtained. Participants who meet the eligibility requirements of the study and 
are willing to continue in the study, will return for an Annual Sampling Visit. During 

UCL / CHDI Foundation, Inc. 
 
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Date and version: 27 October 2021, Version No. 004.1  
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that visit, biosamples will be collected following a fast of at least 6 hours, or 
overnight: blood will be obtained via venipuncture and CSF will be obtained via 
lumbar puncture. Some participants may be invited to return for an Optional Repeat 
Sampling Visit approximately 4-8 weeks after the Annual Sampling Visit during their 
first year of enrollment.   
The annual visits are at regular intervals after the first Annual Screening Visit (i.e. at 
1, 2, 3 years and so on) ± 2 months. Participants will be encouraged to complete all 
annual visits; however, they are under no obligation to take part and will be able to 
skip annual visit without being discontinued from the study. Participants who do not 
come for an Annual Sampling Visit for three consecutive years will be discontinued 
from the study, but they may enroll again at a later date, if they so consent. 
Participants who have already completed HDClarity Sampling Visits under earlier 
versions of this protocol may also participate in the longitudinal study if they meet the 
eligibility criteria.  
Participant cohorts are as follows and recruitment will be balanced across cohorts as 
far as possible. However, recruitment to the moderate and advanced manifest HD 
cohorts is expected to be approximately 50% of recruitment to other cohorts and 
recruitment to the juvenile manifest and incomplete penetrance HD cohorts will be 
independent of recruitment to other cohorts:  
1. Healthy controls 
2. Early Pre-manifest HD 
3. Late Pre-manifest HD 
4. Early Manifest HD 
5. Moderate Manifest HD 
6. Advanced Manifest HD 
7. Juvenile Manifest HD  
8. Incomplete Penetrance HD 
 
Diagnosis and main criteria for inclusion: 
Healthy controls as well as Huntington's disease gene expansion carriers (HDGECs) 
will be enrolled. The latter will include seven groups: early pre-manifest, late pre-
manifest HD, early HD, moderate HD, advanced HD, juvenile HD and incomplete 
penetrance HD. 
Inclusion Criteria: 
1. All eligible participants: 
a. Are capable of providing informed consent or have a legal representative 
authorized to give consent on behalf of the participant, or in the case of underage 
participants (as defined by local regulations in each country), are able to provide 
their informed assent together with consent from a parent or guardian; and 
b. Are capable of complying with study procedures, including fasting, blood 
sampling and lumbar puncture; and 
c. Are participating in the Enroll-HD study; and 
d. Will have had an Enroll-HD visit within three months prior to the Annual 
Screening Visit. 
2. For the Healthy Control group, participants eligible are persons who meet the 
following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 

UCL / CHDI Foundation, Inc. 
 
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Date and version: 27 October 2021, Version No. 004.1  
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b. Have no known family history of HD; or 
c. Have known family history of HD but have been tested for the huntingtin gene 
CAG expansion and are not at genetic risk for HD (CAG < 36). 
3. For the Early Pre-manifest HD group, participants eligible are persons who meet 
the following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 
b. Do not have clinical diagnostic motor features of HD, defined as Unified 
Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score < 4; 
and 
c. Have CAG expansion ≥ 40; and 
d. Have burden of pathology score, computed as (CAG – 35.5) × age, < 250. 
4. For the Late Pre-manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 
b. Do not have clinical diagnostic motor features of HD, defined as Unified 
Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score < 4; 
and 
c. Have CAG expansion ≥ 40; and 
d. Have burden of pathology score, computed as (CAG – 35.5) x age, ≥ 250. 
5. For Early Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 21-75 years of age, inclusive, at the time of consent; and 
b. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic 
Confidence Score = 4; and 
c. Have CAG expansion ≥ 40; and 
d. Have Stage I or Stage II HD, defined as UHDRS Total Functional Capacity 
(TFC) scores between 7 and 13 inclusive. 
6. For Moderate Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 21-75 years of age, inclusive, at the time of consent; and 
b. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic 
Confidence Score = 4; and 
c. Have CAG expansion ≥ 40; and 
d. Have Stage III HD, defined as UHDRS TFC scores between 3 and 6, inclusive. 
7. For Advanced Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 21-75 years of age, inclusive, at the time of consent; and 
b. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic 
Confidence Score = 4; and 
c. Have CAG expansion ≥ 40; and 
d. Have Stage IV HD, defined as UHDRS TFC scores between 0 and 2, inclusive. 
8.  For Juvenile Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are ≥11 years of age at the time of consent; and 
b. Have clinical diagnostic features of juvenile HD, defined as UHDRS Diagnostic 
Confidence Score = 4 aged ≤20 years; and 
c. Have CAG expansion ≥ 40. 

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
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9. For Incomplete Penetrance HD group, participants eligible are persons who meet 
the following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 
b. Have CAG expansion of 36-39. 
 
Exclusion Criteria: 
1. For all groups, participants are ineligible if they meet any of the following exclusion 
criteria: 
a. Use of investigational drugs or participation in a clinical drug trial within 30 days 
prior to any Sampling Visit; or 
b. Current intoxication, drug or alcohol abuse or dependence; or 
c. If using any medications or nutraceuticals, the use of inappropriate (e.g., non-
prescribed) or unstable dose within 30 days prior to any Sampling Visit; or 
d. Significant medical, neurological or psychiatric co-morbidity likely, in the 
judgment of the Site Principal Investigator, to impair participant's ability to 
complete study procedures, or likely to reduce the utility of the samples and 
data for the study of HD; or 
e. Needle phobia, frequent headache, significant lower spinal deformity or major 
surgery; or 
f. Antiplatelet or anticoagulant therapy within 14 days prior to any Sampling 
Visit, including but not limited to: aspirin (>81mg), clopidogrel, dipyridamole, 
warfarin, dabigatran, rivaroxaban and apixaban; or 
g. Clotting or bruising disorder; or 
h. Screening blood test results more than 10% outside the lab's normal range for 
the following: white cell count, neutrophil count, lymphocyte count, 
hemoglobin (Hb), platelets, prothrombin time (PT) and activated partial 
thromboplastin time (APTT), or any combination of blood test results that the 
Site Principal Investigator deems to be of clinical significance; or 
i. Screening blood test results for C-reactive protein (CRP)>2× upper limit of 
normal; or 
j. Predictable non-compliance as assessed by Site Principal Investigator; or 
k. Inability or unwillingness to undertake any of the study procedures; or 
l. Exclusion during history or physical examination, final decision to be made by 
the Site Principal Investigator; including but not limited to: 
i. any reason to suspect abnormal bleeding tendency, e.g. easy bruising, 
petechial rash; or 
ii. any reason to suspect new focal neurological lesion, e.g. new headache, 
optic disc swelling, asymmetric focal long tract signs; or 
iii. any other reason that, in the clinical judgment of the Site Principal 
Investigator, it is felt that lumbar puncture performed per this protocol and 
associated manuals is unsafe without brain imaging; or 
iv. positive urine pregnancy test at any screening or sampling visit for females 
of child bearing potential; or 
m. Lumbar puncture procedure performed for any reason in the previous 30 days; 
or  
n. Any SAE deemed related to the LP procedure or blood patch necessitated after 
LP; or 

UCL / CHDI Foundation, Inc. 
 
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o. Any other complication or experience during or after any previous lumbar 
puncture that, in the clinical judgement of the Site Principal Investigator, is 
likely to pose an unacceptable risk for future lumbar puncture.  
Sample Size: 
The CSF and plasma samples collected in this study will be the basis of future 
biomarker analysis studies. Each of those studies will require a specific power 
calculation to determine how many samples to include in the analysis.  
Only sites with access to in-patient facilities will likely be able to recruit volunteers 
with advanced HD, so those numbers will likely be smaller. 
For some biomarkers, it may be important to understand the stability of the biomarker 
within participants over relatively short time periods (test-retest reliability). Thus, up 
to approximately 20% participants will be invited to return for an Optional Repeat 
Sampling Visit 4-8 weeks after their Annual Sampling Visit during the first year of 
enrollment. Other biomarker discovery and analysis, e.g. analysis of disease 
progression, may require comparison of samples at longer intervals and these will be 
available from the longitudinal sampling visits. 

UCL / CHDI Foundation, Inc. 
 
Study Protocol: HDClarity (UCL-CHDI-1) 
Date and version: 27 October 2021, Version No. 004.1  
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Table of Contents 
 
Synopsis ........................................................................................................................ 5 
Table of Contents ............................................................................................................... 10 
 
List of Abbreviations and Definitions of Terms ......................................................... 13 
 
Roles & Responsibilities ............................................................................................. 14 
3.1 
Names, affiliations and roles of protocol contributors: ..................................... 14 
3.2 
Contact Information for the Study Sponsor ...................................................... 14 
3.2.1 Postal address non-European sites ........................................................... 14 
3.2.2 Postal address European sites .................................................................. 14 
3.3 
CHDI contact information ................................................................................. 15 
3.4 
Medical Monitor contact information ............................................................... 15 
 
Introduction ................................................................................................................. 16 
4.1 
Background and Rationale ................................................................................ 16 
4.2 
Rationale for Current Study .............................................................................. 16 
4.2.1 Ethical Considerations ............................................................................. 16 
 
Study Objectives ......................................................................................................... 17 
5.1 
Primary Objective.............................................................................................. 17 
5.2 
Secondary Objective(s) ..................................................................................... 17 
 
Study Design ............................................................................................................... 18 
6.1 
Overall Study Design ........................................................................................ 18 
 
Study Population ......................................................................................................... 18 
7.1 
Diagnosis and Main Selection Criteria .............................................................. 19 
7.1.1 Inclusion Criteria ..................................................................................... 19 
7.1.2 Exclusion Criteria .................................................................................... 20 
7.2 
Criteria for Termination of the Study ................................................................ 21 
 
Study Procedures ........................................................................................................ 22 
8.1 
Description of Study Assessments .................................................................... 22 
8.1.1 
Annual Screening Visit ............................................................................. 24 
8.1.2 
Annual Sampling Visit .............................................................................. 24 
8.1.2.1 Participant Discharge .......................................................................... 25 
8.1.3 Follow-up Telephone Call ........................................................................ 25 
8.1.4 Optional Repeat Sampling Visit ............................................................... 25 
8.1.4.1 Participant Discharge .......................................................................... 26 

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8.1.5 Follow-up Telephone Call 2 ..................................................................... 26 
 
Sample Collection Procedures .................................................................................... 26 
9.1 
Lumbar CSF Collection..................................................................................... 26 
9.2 
Venous Blood Collection ................................................................................... 27 
 Sample Processing Procedures ................................................................................... 27 
10.1 CSF Sample Processing..................................................................................... 27 
10.2 Serum Sample Processing ................................................................................. 27 
10.3 Plasma Sample Processing ................................................................................ 27 
 Sample storage and shipment ..................................................................................... 27 
 Sample Quality Control .............................................................................................. 27 
 Medical Monitoring .................................................................................................... 27 
 Adverse Event Reporting and Documentation ........................................................... 27 
14.1 Adverse Events .................................................................................................. 27 
14.1.1 AE Severity Grading ................................................................................ 28 
14.1.2 AE Relationship to study procedures ....................................................... 28 
14.2 Serious Adverse Events ..................................................................................... 28 
14.2.1 Serious Adverse Event Reporting ............................................................ 29 
14.3 Reporting incidents............................................................................................ 29 
14.4 Post-study Follow-up of Adverse Events .......................................................... 30 
 Statistical Methodology .............................................................................................. 30 
15.1 Determination of Sample Size ........................................................................... 30 
 Study Management ..................................................................................................... 31 
16.1 Roles and responsibilities .................................................................................. 31 
16.2 Ethics and Regulatory Considerations .............................................................. 31 
16.2.1 Audits and Inspections ............................................................................. 31 
16.2.2 Ethics Committee Approval ..................................................................... 31 
16.3 Insurance ........................................................................................................... 31 
16.4 Informed Consent Procedure ............................................................................. 31 
16.5 Data Collection, Retention and Monitoring ...................................................... 32 
16.5.1 Data Entry/Electronic Data Capture System............................................ 32 
16.5.2 Data Quality Control and Reporting ........................................................ 32 
16.5.3 Archival of Data ....................................................................................... 33 
16.5.4 Investigator Site Files .............................................................................. 33 
16.5.5 Source Documents ................................................................................... 33 

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16.5.6 Monitoring ............................................................................................... 33 
16.5.7 Data transfer ............................................................................................. 33 
16.6 Biological samples (handling, processing and storage) .................................... 34 
16.7 Amendments ...................................................................................................... 34 
16.8 Record Keeping ................................................................................................. 34 
16.8.1 Participant Health Information ................................................................ 34 
16.8.2 Retention of Study Documents ................................................................ 35 
16.9 Reporting ........................................................................................................... 35 
 Appendix A – Site Principal Investigator Obligations ................................................ 36 
 References ................................................................................................................... 38 
 

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Date and version: 27 October 2021, Version No. 004.1  
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
Adverse Event 
APTT 
Activated partial thromboplastin time 
CAG 
Cytosine-adenine-guanine codon whose count in the HTT gene 
determines the genetic diagnosis of HD 
CRP 
C-reactive protein 
CSF  
Cerebrospinal fluid 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture system 
ERB 
Ethics Review Board 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
Hb 
Hemoglobin 
HD 
Huntington's disease 
HDGEC 
Huntington's disease gene expansion carrier 
HTT 
huntingtin protein 
ICH Guidelines 
International Conference on Harmonisation Guidance for Industry 
IRB 
Institutional Review Board 
KMO 
kynurenine mono-oxygenase 
KP 
kynurenine pathway 
PT 
Prothrombin time 
SAE 
Serious Adverse Event 
TFC 
Total Functional Capacity 
TMS 
Total Motor Score 
UHDRS 
Unified Huntington's Disease Rating Scale 
 

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Study Protocol: HDClarity (UCL-CHDI-1) 
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Roles & Responsibilities 
3.1 
Names, affiliations and roles of protocol contributors: 
Bernhard Landwehrmeyer, MD PhD; CHDI Management and Ulm 
University Hospital; Funding Source Medical Consultant 
Blair Leavitt, MD; The University of British Columbia, Centre for 
Molecular Medicine and Therapeutics; Site Principal Investigator 
Jan Lewerenz, MD; Ulm University Hospital; Site Principal Investigator 
Cristina Sampaio, MD PhD; CHDI Management; Funding Source Chief 
Clinical Officer 
Edward Wild, MD; University College London, Institute of Neurology; 
Chief Investigator 
Swati Sathe, MD MS; Funding Source Medical Director 
3.1.1. Acknowledgement of Previous Contributors:  
Beth Borowsky, PhD; previously CHDI Management; Funding Source 
Science Director - key contributor protocol up to VerNo002 
Cheryl Fitzer-Attas, PhD, MBA; previously CHDI Management; Funding 
Source Vice President Clinical Research 
 
3.2 
Contact Information for the Study Sponsor  
Joint Research Office  
1st Floor Maple House (Suite B)  
149 Tottenham Court Road  
London W1T 7DN 
 
Phone: +44 203 447 7430  
Fax: +44 203 108 2312 
Email: uclh.randd@nhs.net 
Website www.ucl.ac.uk/jro 
3.2.1 
Postal address  
 
Joint Research Office, UCL, Gower Street,  
London WC1E 6BT  
 
3.2.2 
Postal address European sites requiring EU legal 
representation 
UCL Research Limited, 70 Sir John Rogerson's Quay, Dublin 2,  
D02 R296, Ireland 
 

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3.3 
CHDI contact information 
MEDICAL CONTACT 
Cristina Sampaio, MD, PhD, Chief Clinical Officer 
CHDI Management, Inc. 
155 Village Boulevard, Suite 200 
Princeton, NJ 08540, USA 
Phone: +1 609 945 9639 
Fax: 
+1 609 452 2160 
E-mail:Cristina.Sampaio@chdifoundation.org 
 
PROJECT MANAGER and STUDY LEAD, CHDI PRIMARY 
CONTACT 
Elena Pak 
CHDI Management, Inc. 
350 Seventh Avenue, Suite 200 
New York, NY 10001, USA 
Phone: +1 212 660 8111 
Fax: 
+1 212 239 2101 
E-mail:elena.pak@chdifoundation.org 
 
 
3.4 
Medical Monitor contact information 
Swati Sathe, MD MS, Medical Director 
CHDI Management, Inc. 
155 Village Boulevard, Suite 200 
Princeton, NJ 08540, USA 
Phone: +1 609 945 9044 
Fax: 
+1 609 452 2160 
E-mail: swati.sathe@chdifoundation.org 
 
 

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Introduction 
4.1 
Background and Rationale 
Huntington's disease (HD) is an autosomal dominant genetic disease, which typically 
manifests beginning in adulthood in the form of movement symptoms, cognitive decline, 
and psychiatric changes (Roos, 2010). Currently the only approved treatment for HD is 
tetrabenazine, but several clinical trials have been initiated and more are expected to 
launch in the next few years to explore novel therapeutic approaches to treating this 
disease. In preparation for such trials, biomarkers are needed to evaluate: (1) how well 
these novel therapeutics reach their intended target and have a biological effect 
(pharmacodynamic markers); (2) the effectiveness of these novel therapeutics at 
improving clinical signs and symptoms (efficacy biomarkers); and (3) the state of disease 
participants are in throughout the trial (disease progression biomarkers). Cerebrospinal 
fluid (CSF) is an ideal fluid compartment for assessing HD biomarkers, particularly 
pharmacodynamics markers, due to its proximity to the brain. 
Several therapeutic approaches focused on lowering huntingtin protein (HTT) in the brain 
are currently pursued, and studies in animals suggest this is a promising approach 
(Kordasiewicz, 2012). However, one of the key tools needed to pursue such approaches in 
humans is the ability to demonstrate that the intervention did lower HTT levels in the 
brain. Fortunately, assays are being developed that can detect HTT in CSF. We propose to 
further the development and validation of CSF HTT assays by measuring HTT levels in 
CSF and plasma from those with manifest HD, premanifest HDGECs and healthy 
controls. The results of these studies will lead to the establishment of the best practices for 
measuring HTT in CSF before and after HTT lowering therapies. Furthermore, 
longitudinal data will help establish the value of mutant HTT in CSF as disease 
progression and as a prognostic or predictive marker. 
Several CSF and plasma HD biomarker discovery programs have resulted in the 
generation of a “hot list” of proteins potentially differentially expressed in HD. While 
promising, this list needs to be replicated in a new sample set, potentially with more 
quantitative assays. We propose to use samples collected in the current study to further 
explore the potential of these and other proposed biomarkers to become validated HD 
CSF and plasma biomarkers. 
For example, evidence from preclinical animal studies as well as post-mortem human 
brain studies suggests that the kynurenine pathway (KP) may be abnormally regulated in 
HD (Guidetti et al., 2004). To further investigate the potential dysregulation of the 
pathway, and inter-participant variability of the dysregulation, we propose to measure 
levels of some of the key KP metabolites. 
4.2 
Rationale for Current Study 
With promising new therapeutic trials underway and more expected to begin in the next 
few years, exploration of potential biomarkers needs to be accelerated now. The current 
study will provide a repository of CSF from well-characterized HDGECs spanning the 
disease spectrum in order to expedite the research into biomarkers for HD. 
4.2.1 
Ethical Considerations 
Institutional review board and ethics review board 

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Sites will be responsible for obtaining all appropriate approvals, supported by a CHDI-
approved informed consent form. ERB and/or IRB approval will be sought for each site in 
each country as per their regulations prior to the start of the study activities at that site. For 
example, as relates to any UK participants or UK National Health Service (NHS) site, no 
study activities involving such UK participants or any such NHS site will occur until an 
application covering all proposed activities at any such NHS site or involving such UK 
participants, submitted via the Integrated Research Application System (IRAS), has been 
approved from an NHS Research Ethics Committee (REC). 
Informed consent procedure 
All participants must give informed consent, or assent if underage, prior to undertaking 
study procedures and these informed consents and assents must be obtained by clinical 
site staff using approved processes. Signed consent and assent forms will be maintained in 
a secure designated location at the site.  
Participants will consent or assent for 3 years initially, equivalent to 4 Annual Screening 
and 4 Annual Sampling Visits (i.e. year 0, 1, 2 and 3). They may renew their informed 
consent or assent in the fourth year in order to continue participating in the study.  
Participant safety 
The procedures for performing lumbar punctures and venous blood draws have been 
designed to maximize participant safety. 
Participant risk 
Study-related risks are explained in the informed consent document, including the 
parental consent for underage participants. In particular, the following risks may be 
associated with lumbar puncture: pain; headache, infection, bleeding and nerve root 
damage. Safety data collected in the first two years of HDClarity shows that the overall 
risk of moderate headache after a lumbar puncture was about 6% and approximately 9% 
of procedures resulted in mild headaches. The risk of a severe headache was less than 
0.2%.  Most headaches resolve spontaneously but occasionally a headache may be 
persistent; in rare cases this may necessitate treatment, which may include a second 
procedure (a blood patch), carried out in a clinical setting. 
See Appendix A – Site Principal Investigator Obligations for additional information. 
 
Study Objectives 
The overall objective of this study is to generate a high quality CSF sample collection that 
can be used to identify and validate biomarkers for HD clinical development.  
CSF and blood samples will be collected from select sites throughout the world using a 
standardized protocol. Careful collection of clinical and phenotypic data on each donor 
will enable us to appropriately select subsets of samples for each set of experimental 
assays.  
5.1 
Primary Objective 
The primary objective of this study is to generate a high quality CSF sample collection for 
evaluation of biomarkers and pathways that will enable the development of novel 
treatments for HD. 
5.2 
Secondary Objective(s) 
The secondary objectives of this study are: 

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• To generate a high quality plasma sample collection matching the CSF collections, 
which will also be used to evaluate biomarkers and pathways of relevance to HD 
research and development. 
• To collect phenotypic and clinical data for each participant. 
 
Study Design 
6.1 
Overall Study Design 
This is a Phase 0 observational study. 
Recruitment: Participants will be recruited at multiple sites in the UK, Europe, North 
America, South America and Australasia from among participants in the Enroll-HD study 
who will have had an Enroll-HD study visit within three months prior to the Annual 
Screening Visit. 
Study Visits: Participants will attend two annual study visits: an Annual Screening Visit 
followed by an Annual Sampling Visit. During the Annual Screening Visit, which may 
coincide with an Enroll-HD visit, medical history, clinical and phenotypic data (including 
a screening blood sample) will be obtained. These data will determine participant 
eligibility for participation in the study and will be used in the analysis of biomarker data. 
Participants meeting the eligibility requirements of the study and willing to continue in 
the study, will return for an Annual Sampling Visit within 30 days of the Annual 
Screening Visit. During that visit, biosamples will be collected following a fast of at least 
6 hours, or overnight: blood will be obtained via venepuncture and CSF will be obtained 
via lumbar puncture. Participants will be contacted by telephone approximately 24-72 
hours after the Annual Sampling Visit. Some participants may be invited to return for an 
Optional Repeat Sampling Visit 4-8 weeks following the Annual Sampling Visit 
during their first year of enrolment. 
Participants will attend annual visits at regular intervals after the first Annual Screening 
Visit (i.e. at 1, 2, 3 years and so on) ± 2 months. Participants will be encouraged to 
complete all annual visits; however, they are under no obligation to take part and will be 
able to skip an annual visit without being discontinued from the study. Participants who 
do not come for an Annual Sampling Visit for three consecutive years will be 
discontinued from the study, but they may enroll again at a later date, if they so consent. 
Participants who have already completed HDClarity Sampling Visits under earlier 
versions of this protocol may also participate in the longitudinal study if they meet the 
eligibility criteria. Enroll-HD visits will provide the clinical data for this study.   
Biosample Preparation: Samples will be processed and stored as described in Sections 
10.1, 10.2 and 10.3 until ready for analysis. 
Laboratory analyses: Samples will be shipped to laboratories, as directed by CHDI, for 
multiple HD research investigations. 
Statistical analysis: For each set of laboratory analyses conducted, a statistical analysis 
plan will be finalized before samples are sent to the laboratory conducting the studies. 
 
Study Population 
Eight participant cohorts will be included in the study and recruitment will be balanced 
across cohorts as far as possible. However, recruitment to the moderate and advanced 
manifest HD cohorts is expected to be approximately 50% of recruitment to other cohorts 

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and recruitment to the juvenile manifest and incomplete penetrance HD cohorts will be 
independent of recruitment to other cohorts: 
1. Healthy controls 
2. Early Pre-manifest HD 
3. Late Pre-manifest HD 
4. Early Manifest HD 
5. Moderate Manifest HD 
6. Advanced Manifest HD 
7. Juvenile Manifest HD 
8. Incomplete Penetrance HD 
7.1 
Diagnosis and Main Selection Criteria 
Both male and female participants will be enrolled in the study. Eligible participants 
include healthy controls, people who are in the early pre-manifest and late pre-manifest 
stage of HD, people diagnosed with early HD, moderate HD or advanced HD, people 
with incomplete penetrance HD, and people diagnosed with juvenile HD.  
7.1.1 
Inclusion Criteria 
1. All eligible participants: 
a. Are capable of providing informed consent or have a legal representative 
authorized to give consent on behalf of the participant, or in the case of underage 
(as defined by local regulations in each country) participants, are able to provide 
their informed assent together with consent from a parent or guardian; and 
b. Are capable of complying with study procedures, including fasting, blood sampling 
and lumbar puncture; and 
c. Are participating in the Enroll-HD study; and 
d. Will have had an Enroll-HD visit within three months prior to the Annual 
Screening Visit. 
2. For the Healthy Control group, participants eligible are persons who meet the following 
criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 
b. Have no known family history of HD; or 
c. Have known family history of HD but have been tested for the huntingtin gene 
CAG expansion and are not at genetic risk for HD (CAG < 36). 
3. For the Early Pre-manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 
b. Do not have clinical diagnostic motor features of HD, defined as Unified 
Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score < 4; 
and 
c. Have CAG expansion ≥ 40; and 
d. Have burden of pathology score, computed as (CAG – 35.5) × age, < 250. 
4. For the Late Pre-manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and 
b. Do not have clinical diagnostic motor features of HD, defined as Unified 
Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score < 4; 
and 
c. Have CAG expansion ≥ 40; and 

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d. Have burden of pathology score, computed as (CAG – 35.5) x age, ≥ 250. 
5. For Early Manifest HD group, participants eligible are persons who meet the following 
criteria: 
a. Are 21-75 years of age, inclusive, at the time of consent; and 
b. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic 
Confidence Score = 4; and 
c. Have CAG expansion ≥ 40; and 
d. Have Stage I or Stage II HD, defined as UHDRS Total Functional Capacity (TFC) 
scores between 7 and 13 inclusive. 
6. For Moderate Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 21-75 years of age, inclusive, at the time of consent; and 
b. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic 
Confidence Score = 4; and 
c. Have CAG expansion ≥ 40; and 
d. Have Stage III HD, defined as UHDRS TFC scores between 3 and 6, inclusive. 
7. For Advanced Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 21-75 years of age, inclusive, at the time of consent; and 
b. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic 
Confidence Score = 4; and 
c. Have CAG expansion ≥ 40; and 
d. Have Stage IV HD, defined as UHDRS TFC scores between 0 and 2, inclusive. 
8. For Juvenile Manifest HD group, participants eligible are persons who meet the 
following criteria: 
a. Are ≥11 years of age at the time of consent; and 
b. Have clinical diagnostic features of juvenile HD, defined as UHDRS Diagnostic 
Confidence Score = 4 aged ≤ 20 years; and 
c. Have CAG expansion ≥ 40 
9. For Incomplete Penetrance HD group, participants eligible are persons who meet the 
following criteria: 
a. Are 18-75 years of age, inclusive, at the time of consent; and  
b. Have CAG expansion of 36-39  
7.1.2 
Exclusion Criteria 
1. For all groups, participants are ineligible if they meet any of the following exclusion 
criteria: 
a. Use of investigational drugs or participation in a clinical drug trial within 30 days 
prior to any Sampling Visit; or 
b. Current intoxication, drug or alcohol abuse or dependence; or 
c. If using any medications or nutraceuticals, the use of inappropriate (e.g., non-
prescribed) or unstable dose within 30 days prior to any Sampling Visit; or 
d. Significant medical, neurological or psychiatric co-morbidity likely, in the 
judgment of the Site Principal Investigator, to impair participant's ability to 
complete study procedures, or likely to reduce the utility of the samples and data 
for the study of HD; or 

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e. Needle phobia, frequent headache, significant lower spinal deformity or major 
surgery; or 
f. Antiplatelet or anticoagulant therapy within 14 days prior to any Sampling Visit, 
including but not limited to: aspirin (>81mg), clopidogrel, dipyridamole, warfarin, 
dabigatran, rivaroxaban and apixaban; or 
g. Clotting or bruising disorder; or 
h. Screening blood test results more than 10% outside the lab's normal range for the 
following: white cell count, neutrophil count, lymphocyte count, hemoglobin 
(Hb), platelets, Prothrombin time (PT) and activated partial thromboplastin time 
(APTT), or any combination of blood test results that the Site Principal 
Investigator deems to be of clinical significance; or 
i. Screening blood test results for C-reactive protein (CRP) >2× upper limit of 
normal; or 
j. Predictable non-compliance as assessed by the Site Principal Investigator; or 
k. Inability or unwillingness to undertake any of the study procedures; or 
l. Exclusion during history or physical examination, final decision to be made by the 
Site Principal Investigator; including but not limited to: 
i 
any reason to suspect abnormal bleeding tendency, e.g. easy bruising, 
petechial rash; or 
ii any reason to suspect new focal neurological lesion, e.g. new headache, 
optic disc swelling, asymmetric focal long tract signs; or 
iii any other reason that, in the clinical judgment of the Site Principal 
Investigator, it is felt that lumbar puncture performed per this protocol and 
associated manuals is unsafe without brain imaging; or 
iv positive urine pregnancy test at any screening or sampling visit for females 
of child bearing potential; or 
m. Lumbar puncture procedure performed for any reason in the previous 30 days; or 
n. Any SAE deemed related to the LP procedure or blood patch necessitated after LP; 
or  
o. Any other complication or experience during or after any previous lumbar puncture 
that, in the clinical judgement of the Site Principal Investigator, is likely to pose an 
unacceptable risk for future lumbar puncture. 
 
7.2 
Criteria for Termination of the Study 
The Chief Investigator may terminate this study prematurely as follows: (a) on an 
immediate basis for any reason reasonably related to the health or safety of the 
participants and (b) upon 90 days written notice to CHDI for any other reason. CHDI may 
terminate this study prematurely for any reason. The Sponsor and Institutional Review 
Board(s) (IRBs)/Ethics Review Board(s) (ERBs) must be informed promptly. 
If the study is prematurely terminated or suspended for any reason, the Site Principal 
Investigator/institution should promptly inform the study participants and should assure 
appropriate follow-up for them. 

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Study Procedures 
Participants will attend two annual study visits, an Annual Screening Visit followed by an 
Annual Sampling Visit. They may also attend an optional visit during their first year of 
enrollment, an Optional Repeat Sampling Visit.  Participants will attend annual visits at 
regular intervals after the first Annual Screening Visit (i.e. at 1, 2, 3 years and so on) ± 2 
months. The study procedures for each visit type are described in the Schedule of Events 
table below. 
 
8.1 
Description of Study Assessments 
The Annual Screening and Annual Sampling Visits should be no more than 30 days apart.  
The Annual Screening Visit may occur on the same day as an Enroll-HD visit. The 
Optional Repeat Sampling Visit will occur within 4-8 weeks of the Annual Sampling 
Visit during the first year of enrollment. Participants will be encouraged to complete all 
annual visits; however, they are under no obligation to take part and will be able to skip 
annual visits without being discontinued from the study for up to three years. 
Information regarding occurrence of adverse events (AEs) and Serious Adverse Events 
(SAEs) will be captured each year in the period from the Annual Screening Visit until the 
follow-up phone call after the associated Annual Sampling Visit (or Optional Repeat 
Sampling visit, if applicable). Duration (start and stop dates and times), severity/grade, 
outcome, treatment and relation to study procedures will be recorded on the electronic 
case report form (eCRF). 

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HDCLARITY SCHEDULE OF EVENTS 
 
Year 01 
Years 1, 2, 31  
Visit Type 
Annual Screening 
Annual Sampling 
Optional Repeat 
Sampling 
Annual Screening 
Annual Sampling 
Visit Window 
-30 to -1 days 
Day 0 
Day 28 - 56 
Annually ± 2 
months 
Within 30 days of 
Annual Screening 
Visit 
Study Procedure 
 
 
 
 
 
Informed Consent / Assent 
X 
 
 
 
 
Confirm Continued Consent / Assent 
 
X 
X 
X 
X 
Inclusion/Exclusion Criteria review 
X 
X 
X 
X 
X 
Demographics update 
X 
 
 
X 
 
Confirm Enroll-HD core assessments 
completed within last three months  
X 
 
 
X 
 
Brief Physical Exam 
X 
X 
X 
X 
X 
Medical History update 
X 
X 
X 
X 
X 
Prior/Concomitant Medication update 
X 
X 
X 
X 
X 
Full Neurological Examination 
X 
 
 
X 
 
Focused Neurological Examination 
 
X 
X 
 
X 
Total Motor Score (TMS) 
 
X 
X 
 
X 
Vital Signs (BP, pulse, body temp) 
 
X 
X 
 
X 
Safety Laboratory Assessments  
X 
 
 
X 
 
Urine Pregnancy Test2 
X 
X 
X 
X 
X 
Adverse Events (AE) 
 
X 
X 
 
X 
Final Eligibility Check 
 
X 
X 
 
X 
Lumbar CSF Collection 
 
X 
X 
 
X 
Venous Blood Draw3 
 
X 
X 
 
X 
CSF and Blood Sample Processing 
 
X 
X 
 
X 
CSF QC Processing 
 
X 
X 
 
X 
Telephone Follow-Up within 1-3 days 
(concomitant medication and AEs) 
 
X 
X 
 
X 
 
1 This sequence of visits will continue such that Informed Consent/Assent will be sought again every fourth year 
2 Urine pregnancy test to be performed for females of child bearing potential unless the participant is post-menopausal or not sexually active 
3 Obtain venous blood sample immediately after CSF collection is complete

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8.1.1 
Annual Screening Visit 
• The study will be described in detail to prospective participants and informed 
consent or assent will be obtained at the first Annual Screening Visit. Continued 
consent will be confirmed at all subsequent Annual Screening Visits. 
• Medical history update since the last Enroll-HD study visit, including medication 
history and co-morbidities, is obtained. 
• Demographic information update since the last Enroll-HD study visit. 
• Weight measurement (only if weight appears to vary significantly (>3kg/6.5lb) 
since last Enroll-HD visit). 
• Perform a full neurological examination as described in the HDClarity Laboratory 
Manual, as well as a brief general physical examination. Evidence of possible 
bleeding tendency such as bruises or petechial rash should be noted. 
• Urine pregnancy test for females of child bearing potential (excludes females who 
are post-menopausal or not sexually active). 
• Up to 15 ml of venous blood is drawn according to local clinical standards and 
procedures, and routine blood tests performed by a local accredited clinical 
laboratory: 
o Full blood count 
o Clotting profiles: PT and APTT 
o CRP 
If the blood count or clotting profiles are more than 10% outside the lab's normal range 
for the following: white cell count, neutrophil count, lymphocyte count, hemoglobin (Hb), 
platelets, prothrombin time (PT) and activated partial thromboplastin time (APTT), or if 
CRP is greater than 2× the upper limits of normal the participant will not be booked for an 
Annual Sampling Visit. The Site Principal Investigator will act on any abnormalities 
according to clinical judgment. 
If participants do not fulfill all inclusion criteria, they may be rescheduled to repeat some 
or all of the screening assessments above with the prior approval of the Chief Investigator. 
If these assessments confirm all the eligibility requirements are met for the study, a date 
will be given via a telephone call for the Annual Sampling Visit. 
8.1.2 
Annual Sampling Visit 
• Participants will be required to fast and drink only water for at least six hours, or 
overnight, before the scheduled time of the Annual Sampling Visit. Compliance 
with instructions to fast is recorded. 
• If participant has not complied with pre-sampling instructions such as fasting or 
medications, or if the Site Principal Investigator deems the sampling procedure 
unsafe, unwise or unlikely to produce satisfactory samples, the participant may be 
sent home, and the sampling rescheduled at the discretion of the Site Principal 
Investigator. 
• Participant continued consent or assent to participate and eligibility are confirmed 
and recorded. 
• The results of the routine laboratory examination are reviewed and recorded. 

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• Medical and concomitant medication history is updated. 
• Urine pregnancy test for females of child bearing potential (excludes females who 
are post-menopausal or not sexually active). 
• Measurement of vital signs. 
• Weight measurement (only if weight appears to vary significantly (>3kg/6.5lb) 
since last Enroll-HD visit). 
• Any changes to medical history and medication are noted. 
• A focused neurological examination is performed as described in the HDClarity 
Laboratory Manual and the brief physical exam is repeated for safety. 
• The Total Motor Score (TMS) of the UHDRS is performed. 
• Lumbar CSF Collection is performed. (See Section 9.1 for instructions) 
• Venous blood sampling is performed immediately after CSF collection is 
complete. (See Section 9.2 for instructions) 
• AE recording 
• Process CSF, Serum and Plasma samples per Sections 10.1, 10.2 and 10.3, 
respectively. 
• Perform sample quality control (QC) per Section 12. 
• Store samples per Section 11. 
8.1.2.1 
Participant Discharge 
Participants are observed for potential complications as per routine clinical practice and 
discharged once appropriate. Record any AEs. 
Participant is discharged by nurses with instructions for over the counter pain medication 
and hydration in the event of headache. 
8.1.3 
Follow-up Telephone Call 
Participants are contacted within 24 to 72 hours following an Annual Sampling Visit to 
collect any AE and/or concomitant medication data. If an AE is reported and is possibly or 
probably related to study procedures it must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the participant is lost to follow 
up. 
 
8.1.4 
Optional Repeat Sampling Visit 
• This visit is optional. Participant continued consent or assent to participate and 
eligibility are confirmed and recorded. 
• This visit should be scheduled 4 - 8 weeks following the Annual Sampling Visit 
during the first year of enrollment. 
• Participants will be required to fast and drink only water, for at least six hours, or 
overnight, before the scheduled time of the Optional Repeat Sampling Visit. 
Compliance with instructions to fast is recorded. If the participant did not fast, 
they will be sent home, and the procedure rescheduled. 

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• The results of the routine laboratory examination are reviewed and recorded. 
• Urine pregnancy test for females of child bearing potential (excludes females who 
are post-menopausal or not sexually active). 
• Measurement of vital signs. 
• Weight measurement (only if weight appears to vary significantly (>3kg/6.5lb) 
since last Enroll-HD visit). 
• Any changes to medical history and medication are noted. 
• A focused neurological examination is performed as described in the HDClarity 
Lab Manual and the brief physical exam is repeated for safety.  
• The TMS of the UHDRS is repeated. 
• Lumbar CSF Collection is performed. (See Section 9.1 for instructions) 
• Venous blood sampling is performed immediately after CSF collection is 
complete. (See Section 9.2 for instructions) 
• AE recording. 
• Process CSF, Serum and Plasma samples per Sections 10.1, 10.2 and 10.3, 
respectively. 
• Perform sample QC per Section 12. 
• Store samples per Section 11. 
8.1.4.1 
Participant Discharge 
Participants are observed for potential complications as per routine clinical practice and 
discharged once appropriate. Record any AEs. 
Participant is discharged by nurses with instructions for over the counter pain medication 
and hydration in the event of headache. 
8.1.5 
Follow-up Telephone Call 2 
Contact participant 24 to 72 hours following Optional Repeat Sampling Visit to collect 
any AE and/or concomitant medication data. If an AE is reported and is possibly or 
probably related to study procedures it must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the participant is lost to follow 
up. 
 
Sample Collection Procedures 
9.1 
Lumbar CSF Collection 
Up to 20 ml of CSF for participants ≥18 years of age and 5-10 ml for participants <18 
years of age will be collected by a lumbar puncture procedure as described in the 
HDClarity Laboratory Manual, recording the collection time. 
  

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9.2 
Venous Blood Collection 
Venous blood is drawn immediately after CSF collection is complete, recording the time. 
Up to 50 ml of blood from participants ≥18 years of age and 30 ml for participants < 18 
years of age will be collected as described in the HDClarity Laboratory Manual. 
If venepuncture with vacuum tubes proves challenging, a needle and syringe may be used 
and the blood transferred immediately into the vacuum tubes, observing safety 
precautions. 
 
 
Sample Processing Procedures 
10.1 
CSF Sample Processing 
CSF samples must be processed according to the procedures specified in the HDClarity 
Laboratory Manual. 
10.2 
Serum Sample Processing 
Serum samples must be processed according to the procedures specified in the HDClarity 
Laboratory Manual. 
10.3 
Plasma Sample Processing 
Plasma samples must be processed according to the procedures specified in the HDClarity 
Laboratory Manual. 
 
Sample storage and shipment 
Storage and shipment of the samples must be handled according to the procedures 
specified in the HDClarity Laboratory Manual. 
 
Sample Quality Control 
Quality control will be performed on all samples according to the procedures specified in 
the HDClarity Laboratory Manual and/or at a central laboratory.  
 
Medical Monitoring 
The Medical Monitor should be contacted directly to report medical concerns or questions 
regarding safety. The medical monitor can be contacted via email at 
swati.sathe@chdifoundation.org. 
 
Adverse Event Reporting and Documentation 
14.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence during a clinical investigation 
and that does not necessarily have a causal relationship with study treatments or 
procedures. An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the 
administration of study procedures. 
The Site Principal Investigator will probe, via discussion with the participant, for the 
occurrence of AEs during each participant visit, after the Annual Screening Visit, and 
record the information in the site's source documents. AEs will be recorded in the 

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participant eCRF. AEs will be described by duration (start and stop dates and times), 
severity, outcome, treatment and relation to study procedures if applicable, or if unrelated, 
the cause. 
14.1.1 
AE Severity Grading 
The severity of an AE will be graded on a 5-point scale (Common Terminology Criteria 
for Adverse Events v3.0 (CTCAE; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) defined as 
follows: 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
14.1.2 
AE Relationship to study procedures 
The relationship of an AE to the study procedures will be evaluated according to the 
following guidelines: 
Probable: This category applies to AEs which are considered with a high degree of 
certainty to be related to the study procedure. An AE may be considered probably related 
to the study procedure if: 
1. It follows a reasonable temporal sequence from administration of the study 
procedure; 
2. It cannot be reasonably explained by the known characteristics of the participant's 
clinical state, or by environmental or toxic factors; 
3. It follows a known pattern of response to the study procedure; 
Possible: This category applies to those AEs in which the connection with the study 
procedure appears unlikely but cannot be ruled out with certainty. An AE may be 
considered as possibly related if it has at least two of the following: 
1. It follows a reasonable temporal sequence from the study procedure 
2. It may readily have been produced by the participant's clinical state, or by 
environmental or toxic factors; 
3. It follows a known response pattern to the study procedure. 
Unrelated: This category applies to those AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (disease, environment, etc.) and do not meet the 
criteria for study procedure relationship listed under possible or probable. 
14.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as any AE that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 

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• 
a congenital anomaly/birth defect 
• 
any other serious medical occurrence  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the participant or require intervention to 
prevent one of the outcomes listed. 
An AE is considered to be life-threatening if, in the view of the Site Principal 
Investigator, the participant was at immediate risk of death from the reaction as it 
occurred. It does not include a reaction that, had it occurred in a more serious form, might 
have caused death. 
Serious Adverse Events will be documented from the point of enrollment until the 
participant is exited from the study. If a participant enrolls multiple times, AEs and SAEs 
will be documented from the point of each new consent until the final study visit for that 
enrollment.  
Information recorded and reported shall include:   
• 
A description of the event 
• 
the date of event onset 
• 
The relatedness of the event to the procedure 
• 
The expectedness of the event 
• 
The outcome of the event 
• 
The date the event was first noticed by, or reported to the Site Principal Investigator 
All ongoing Serious Adverse Events will be followed-up until the last study visit and post 
study follow-up is described in Section 14.4 below. 
14.2.1 
Serious Adverse Event Reporting 
SAEs (as defined in Section 15.2) must be reported to the designated Medical Monitor 
immediately, and also to the Sponsor by email, and in no case later than within 24-hours 
of awareness of the event. 
All SAEs that occur (whether or not related to study procedures) will be documented. The 
collection period for all SAEs will begin from the Annual Sampling Visit and end after 
procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local IRB/ERB, 
the Site Principal Investigator will report SAEs to the IRB/ERB. 
14.3 
Reporting incidents 
An incident in a research study is: 
• Something that should not have happened OR 
• Something that should have happened but didn't which, in either case, 
significantly affects any of the following: 
• the rights and wellbeing of the study participant,  
• the scientific value of the study, 

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• the compliance of the study with all applicable legal rules or ethics guidance 
including, as applicable, the Data Protection Act, the General Data Protection 
Regulation, and the Human Tissue Act, or 
• the reputation of the Sponsor. 
This includes a requirement to report all serious breaches of protocol or GCP (if 
applicable). 
All incidents must be reported through the appropriate host site incidents reporting 
system. For any host site where no United Kingdom National Health Service Trust is 
involved, the incident should be reported by completing the “Incident Report Form” that 
may be found at http://www.ucl.ac.uk/jro/postapproval.  
14.4 
Post-study Follow-up of Adverse Events 
All AEs, including clinically significant physical examination findings and SAEs, must be 
recorded in the Electronic Data Capture system (EDC) and any AE that is possibly or 
probably related to study procedures must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the participant is lost to follow 
up. If resolved, a resolution date should be documented on the eCRF and in the source 
documents. The Site Principal Investigator is responsible for ensuring that follow up 
includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals as is 
medically indicated. 
 
Statistical Methodology 
15.1 
Determination of Sample Size 
The CSF and plasma samples collected in this study will be the basis for future 
biomarker analysis studies. Each of those studies will require a specific power 
calculation to determine how many samples to include in the analysis. However, the 
open-ended nature of biomarker discovery and validation and the purpose of HDClarity 
as a biorepository favours placing no upper limit on the number of participants that may 
be enrolled. 
While most of the biomarker development focus is on earlier stages of the disease, it may 
also be important to assess some biomarkers at more advanced stages. Only sites with 
access to in-patient facilities will likely be able to recruit this cohort.  
For some biomarkers, it may be important to understand the stability of the biomarker 
within participants over relatively short time periods. Thus, up to approximately 20% 
participants will be invited to return for an Optional Repeat Sampling Visit 4-8 weeks 
after their Annual Sampling Visit during their first year of enrollment. Other biomarker 
discovery and analysis, e.g. analysis of disease progression, may require comparison of 
samples at longer intervals and these will be available from the longitudinal sampling 
visits. 

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Study Management 
16.1 
Roles and responsibilities 
Except where dictated by convention, statute or GCP, the roles and responsibilities of all 
parties involved in the study will be set forth in study site agreements or other contracts or 
subcontracts agreed by the parties concerned. 
16.2 
Ethics and Regulatory Considerations 
This study will be conducted according to Good Clinical Practice (GCP), 21 CFR Part 50, 
(Protection of Human Subjects), 21 CFR Part 56 (Institutional Review Boards), 
International Conference on Harmonisation Guidance for Industry (ICH guidelines), E6 
Good Clinical Practice: Consolidated Guidance, the Nuremberg Code, and the 
Declaration of Helsinki. 
Sites will be responsible for obtaining all appropriate approvals from IRBs/ERBs, 
supported by a CHDI-approved informed consent form. ERB and/or IRB approval will be 
sought for each site in each country as per their regulations prior to the start of study 
activities at that site.  
16.2.1 
Audits and Inspections 
CHDI, regulatory authority, Sponsor or IRB/ERB may visit the study site at any time 
during the study or after completion of the study to perform audits or inspections. The 
purpose of such an audit or regulatory inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities 
were conducted according to the protocol, GCP, ICH guidelines, and any other applicable 
regulatory requirements. Site Principal Investigators should contact the Chief Investigator 
and CHDI immediately if contacted by a regulatory agency about an inspection at their 
site. 
16.2.2 
Ethics Committee Approval 
This protocol and any amendments will be submitted to a properly constituted IRB/ERB, 
in accordance with the ICH guidelines, the applicable European Directives and local legal 
requirements, for approval of the study. Approval must be obtained in writing before the 
first participant can be recruited. 
16.3 
Insurance 
University College London, the Sponsor, holds insurance against claims from participants 
for harm caused by their participation in this study. Participants may be able to claim 
compensation if they can prove that the Sponsor has been negligent. However, if this 
study is being carried out in a hospital, the hospital continues to have a duty of care to the 
participant of the study. The Sponsor does not accept liability for any breach in the 
hospital's duty of care, or any negligence on the part of hospital employees. This applies 
whether the hospital is an NHS Trust or otherwise.  
16.4 
Informed Consent Procedure 
All participants must give informed consent prior to undertaking study procedures and 
these informed consents must be obtained by clinical site staff using approved processes 
according to all applicable laws and regulations on GCP. At a minimum, the consent 
process will involve:  

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1. Provision of written, ERB and/or IRB-approved information about the study to 
potential participants; 
2. Potential participants permitted sufficient opportunity to read the information 
and consider the options without maximum but with a recommended minimum 
of 24 hours;   
3. Potential participants permitted sufficient opportunity to ask questions and 
receive satisfactory answers from the site study team; 
4. Potential participants' comprehension verified before signing a consent form; 
and 
5. The voluntary signing of a consent form and countersigning by the study site 
personnel undertaking the consent process. 
In the event that a site wishes to enroll participants with impaired capacity, specific ERB 
and/or IRB approval will be sought in advance before such participants are enrolled and a 
Legally Authorised Representative will sign on behalf of the participant.  
In the case of underage participants, consent will be obtained from the parent or guardian, 
together with informed assent from the underage participant in compliance with local 
regulations and requirements. 
Informed consent obtained at the beginning of the study will be valid for three years. The 
participants will be reconsented for the study after that every fourth year should they wish 
to continue participation. The participant is encouraged to provide a CSF sample every 
year but are at no obligation to do so. If a participant does not attend an Annual Screening 
and Sampling Visit for consecutive three years, they will be discontinued from the study. 
They can re-enroll in the study if they wish to do so. 
Signed consent forms will be maintained in a secure designated location at the site. 
16.5 
Data Collection, Retention and Monitoring 
16.5.1 
Data Entry/Electronic Data Capture System 
The data are entered electronically via secure internet-based technology. Access to the 
eCRFs is limited by password and can only be authorized by the Chief Investigator and 
issued by the study administrator. Each Site Principal Investigator in this study can only 
see data on participants from their own site. The data managers who are responsible for 
the data quality and integrity have access to all sites' data. Clinical research monitors, who 
are responsible for monitoring data for site that are assigned, can only review the data 
from those sites. They are responsible for study monitoring and ensuring compliance with 
the study protocol. 
16.5.2 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Query reports pertaining to data omissions and discrepancies will be forwarded to the Site 
Principal Investigator and Study Central Coordination for resolution. The study database 
will be updated in accordance with the resolved queries. All changes to the study database 
will be documented. 

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16.5.3 
Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained. Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database. 
UCL and each participating site recognise that there is an obligation to archive study-
related documents at the end of the study (as such end is defined within this protocol). 
The Chief Investigator will archive the study master file at UCL for at least 20 years and 
in line with all applicable legal and statutory requirements. The Site Principal Investigator 
at each participating site agrees to archive his/her respective site's study documents for the 
period of time specified in the site agreement and in line with all applicable legal and 
statutory requirements.  
16.5.4 
Investigator Site Files 
Each site will maintain an Investigator Site File (ISF) containing all applicable regulatory, 
ethical and GCP documentation relating to the conduct of the study at the site. It will be 
the responsibility of each site's Principal Investigator to maintain this ISF.  
16.5.5 
Source Documents 
The Site Principal Investigator should maintain source documents for each participant 
enrolled in the study. Source documents such as local laboratory ranges and reports, 
participant charts and doctors' notes will be kept as part of the participants' medical 
records. For participants who do not have a medical record per se, another method of 
documentation and record keeping will be employed, along with the obligation to retain 
source documents, such as laboratory reports, for the period of time specified in the site 
agreement. Participant files including medical records and signed participant informed 
consent forms must be available for review in the event the site is selected for monitoring, 
audits, or inspections. 
16.5.6 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to 
ethics, protocol adherence, site procedures, integrity of the data, and applicable laws 
and/or regulations. At regular intervals during the study and following completion of the 
study, the Sponsor's study monitors will contact the study site via visits to the site, 
telephone calls, and/or letters in order to review study progress, eCRF completion, and 
address any concerns or questions regarding the study conduct. During monitoring visits, 
the following aspects of study conduct will be carefully reviewed: informed consent of 
participants, participant recruitment, participant compliance with the study procedures, 
source data verification, use of concomitant therapy by participants, AE and SAE 
documentation and reporting, and quality of data. Records pertaining to these aspects are 
expected to be kept current. 
The Site Principal Investigator must make study data accessible to the clinical monitor, to 
other authorized representatives of the Sponsor, and to regulatory inspectors. 
16.5.7 
Data transfer 
In the study, data will be collected from participants in accordance with the participant 
consent form, participant information sheet (as applicable) and of this protocol. 

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The data will be appropriately sent to the data repository held and managed by service 
providers engaged by CHDI for storage and data monitoring, and for the purposes of the 
EU General Data Protection Regulation (GDPR), both CHDI and UCL will act as joint data 
controllers of such data for the study. Both CHDI and UCL have an appointed Data 
Protection Officer to assist with their respective responsibilities and as part of their 
obligations under the GDPR, will provide participants with information about data 
protection and privacy and transfer of data outside of the EU. Participants who were 
consented into the study before GDPR was in force will be provided with a supplemental 
notice containing this information. 
The service providers engaged by CHDI will process, store and dispose of all study data 
in accordance with all applicable legal and regulatory requirements, including, as 
applicable, the Data Protection Act 1998 and the General Data Protection Regulation and 
any amendments thereto. All paper and digital records not uploaded to the study data 
repository will be retained at individual study sites in locked and/or password-protected 
form under the control of the Site Principal Investigators. 
16.6 
Biological samples (handling, processing and storage) 
In the study, cerebrospinal fluid, plasma, serum and cells from CSF will be collected from 
participants in accordance with the participant consent form and participant information 
sheet (as applicable) and shall include all tissue samples or other biological materials and 
any derivatives, portions, progeny or improvements as well as all participant information 
and documentation supplied in relation to them. The biological samples will be 
appropriately sent to BioRep, Via Olgettina, 60, c/o DIBIT 2 - Palazzina San Michele 
20132 Milan – Italy (or such other selected biorepository), for cataloguing and storage of 
the samples to be carried out in accordance with the protocol and the informed consents. 
BioRep (or such other selected biorepository) will process, store and dispose of all 
samples in accordance with all applicable legal and regulatory requirements, including, as 
applicable, the Human Tissue Act 2004 and any amendments thereto. Samples obtained 
from the incomplete penetrance HD cohort will be reserved for specific studies on 
incomplete penetrance alleles.  
16.7 
Amendments 
Any amendments to the protocol will be written and approved by the Chief Investigator 
and CHDI. All amendments must be submitted to the Sponsor and IRB/ERB for approval 
prior to implementing the changes. In some instances, an amendment may require 
changes to the informed consent form, which also must be approved by CHDI and 
submitted for IRB/ERB approval prior to administration to study participants. 
16.8 
Record Keeping 
16.8.1 
Participant Health Information 
The Site Principal Investigator agrees to comply with all applicable laws and regulations 
relating to the privacy of participant health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 
(the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy 
Regulation) and the EU General Data Protection Regulation (GDPR). Where applicable, 
the Site Principal Investigator shall ensure that study participants authorize the use and 
disclosure of protected health information in accordance with HIPAA Privacy Regulation 
and in a form satisfactory to the Sponsor. 

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16.8.2 
Retention of Study Documents 
Study-related records must be retained for the period of time specified in the site 
agreement. The Site Principal Investigator must not destroy any study-related records 
without receiving approval from the Chief Investigator and CHDI. The Site Principal 
Investigator must notify the Chief Investigator in the event of accidental loss or 
destruction of any study records. If the Site Principal Investigator leaves the institution 
where the study was conducted, the Chief Investigator must be contacted to arrange 
alternative record storage options.  
16.9 
Reporting 
After completion of the study, an abbreviated clinical study report will be prepared by the 
Chief Investigator.

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 Appendix A – Site Principal Investigator Obligations 
The study protocol and the final version of the participant informed consent form will be 
approved by an IRB/ERB before enrollment of any participants. The opinion of the 
IRB/ERB will be dated and given in writing. 
The Site Principal Investigator will ensure that the IRB/ERB will be promptly informed 
of all changes in the research activity and of all unanticipated problems including risk to 
participants. The Site Principal Investigator will not proceed with changes to the protocol 
until IRB/ERB approval has been obtained. 
Written informed consent must be given freely and obtained from every participant prior 
to clinical study participation. The rights, safety, and well-being of the study participants 
are the most important considerations and should prevail over interests of science and 
society. 
As described in GCP guidelines, site personnel involved in conducting this study will be 
qualified by education, training, and experience to perform their respective task(s). Site 
personnel will not include individuals who (a) are currently and have not ever been, 
debarred or convicted of a crime for which a person can be debarred or otherwise 
suspended or disqualified under any applicable laws, regulations or professional 
guidelines or (b) have ever been threatened to be debarred or indicted for a crime or 
otherwise engaged in any conduct or activity for which a person can be debarred or 
otherwise suspended or disqualified. Quality assurance systems and procedures will be 
implemented to assure the quality of every aspect of the study. 
IRB/ERB Review/Approval/Reports 
The protocol and informed consent for this study, including advertisements used to recruit 
participants, must be reviewed and approved by an appropriate IRB/ERB prior to 
enrollment of participants in the study. It is the responsibility of the Site Principal 
Investigator to assure that all aspects of the ethical review are conducted in accordance 
with the current Declaration of Helsinki, ICH, GCP, and/or local laws, whichever provide 
the greatest level of protection. A letter documenting the IRB/ERB approval which 
specifically identifies the study/protocol and a list of the committee members must be 
received by the Chief Investigator and CHDI prior to initiation of the study. Amendments 
to the protocol and informed consents will be subject to the same requirements as the 
original protocol and informed consents. 
A progress report with a request for re-evaluation and re-approval will be submitted by 
the Site Principal Investigator to the IRB/ERB at intervals required by the IRB/ERCB. A 
copy of the report will be sent to CHDI and the Sponsor as well as letters of re-evaluation 
and re-approval. 
After completion or termination of the study, the Site Principal Investigator will submit a 
final report to the IRB/ERB and to CHDI, if required. This report should include: 
deviations from the protocol, the number and types of participants evaluated, and 
significant AEs, including deaths. 
Study Documentation 
The Site Principal Investigator is required to maintain complete and accurate study 
documentation in compliance with current GCP standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documentation includes CHDI/Site Principal Investigator correspondence, IRB/ERB 

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correspondence, protocol and amendments, information regarding monitoring activities, 
participant exclusion records, eCRFs, and data queries. 
Confidentiality 
The anonymity of study participants will be protected by using an assigned participant 
number on eCRFs and other documents relating to the participant. Documents that 
identify the participant (e.g., the signed informed consent document) must be maintained 
in strict confidence by the Site Principal Investigator, except to the extent necessary to 
allow auditing by the Food and Drug Administration and other regulatory authorities or 
the clinical monitor and others as described in the informed consent. 
Study Facilities 
The Site Principal Investigator must ensure that there is a robust institutional policy on 
freezer failure that includes checks, alarms, emergency contact details, backup power 
supplies, CO2 cylinders and an infrastructure to transfer samples to an off-site facility if 
necessary. 
 
 

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Kordasiewicz, HB, Sustained Therapeutic Reversal of Huntington's disease by Transient 
Repression of Huntingtin Synthesis. Neuron 2012; 74: 1031. 
Roos, RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010; 5(1):40.