Dose-Response Evaluation of the Investigational Product Cellavita HD After Intravenous Administration in Patients With Huntington's Disease
Phase: PHASE2
Conditions: Huntington Disease
Sponsor: Azidus Brasil

Clinical Protocol: ADORE-DH 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
Confidential document 
Page 1 of 126 
 RESEARCH PROTOCOL 
PROJECT TITLE 
EVALUATION OF THE DOSE-RESPONSE OF CELLAVITA HD 
INVESTIGATIONAL 
PRODUCT 
AFTER 
INTRAVENOUS 
APPLICATION IN PARTICIPANTS WITH HUNTINGTON'S DISEASE  
PROTOCOL CODE 
ADORE-DH (in Portuguese: Avaliação da Dose-Resposta do Produto 
Investigacional CELLAVITA HD em Participantes com Doença de 
Huntington – Evaluation of the dose-response of Cellavita HD 
investigational product after intravenous application in participants with 
Huntington’s disease) 
DOCUMENT 
VERSION 
Amendment 6 dated February 23, 2021 
STUDY PHASE 
Phase II 
INVESTIGATIONAL 
PRODUCT 
Cellavita HD 
SPONSOR 
CELLAVITA PESQUISA CIENTÍFICA LTDA 
Rua Martinho Leardine, 296 
Chácara Silvania,  
Valinhos/ SP - ZIP Code: 13271-650 
ISSUANCE OF THE 
PROTOCOL 
AZIDUS BRASIL PESQUISA CIENTÍFICA E DESENVOLVIMENTO 
LTDA. 
Rua General Osório, 507 
Valinhos/SP - ZIP Code: 13271-130 
Phone/Fax: (19) 3829-6160 
This clinical study protocol contains confidential information owned by Azidus Brasil Pesquisa 
Científica e Desenvolvimento Ltda. and its Sponsor Cellavita Scientific Research Ltda. No 
information contained herein may be reproduced or passed on without the consent of the 
above in writing. 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
Page 2 of 126 
 
I. Sponsor's Signature 
 
My signature, together with the signature of the Investigator, confirms the 
treaty between both parties that the clinical study will be conducted in accordance 
with the protocol and all applicable laws and regulations, including, among others, 
the Guidelines of the International Conference on Harmonization (ICH) for Good 
Clinical Practice (GCP), the Code of Federal Standards (CFR), Resolution 466 of 
December 12, 2012, the FDA document Considerations for the Design of Early-
Phase Clinical Trials of Cellular and Gene Therapy Products - Guidance for Industry 
(2015) applicable privacy laws.  
This protocol was issued according to the international protocol 
preparation guide called 2013 SPIRIT Statement - Standard Protocol Items: 
Recommendations for Interventional Trials. 
 
 
 
 
 
 
 
 
 
Signature - Sponsor  
 
Signature Date  
(dd/mm/yyyy) 
 
 
 
 
 
 
 
 
Name 
and 
Position 
of 
the 
Responsible - Sponsor (printed) 
 
 
 
 
 
 
 
 
 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
Page 3 of 126 
 
II. Statement of the Principal Investigator 
 
My signature, in conjunction with Sponsor's signature, confirms the treaty 
between both parties that the clinical study will be conducted in accordance with the 
protocol and all applicable laws and regulations, including, but not limited to, the 
Guidelines of the International Harmonization Conference (ICH) for Good Clinical 
Practice (GCP), the Code of Federal Standards (CFR), ethical principles originated 
through Resolution 466 of December 12, 2012 and applicable privacy laws. 
Nothing contained in this document is intended to limit a physician's 
authority to provide emergency medical care in accordance with current regulations. I 
will provide copies of the protocol and all relevant information to all professionals 
involved in this study, which are under my responsibility. I will discuss this material 
with these professionals in order to ensure that they are fully informed regarding the 
research product and the conduct of the study. 
I will use the Informed Consent Form (ICF) approved by the Research 
Ethics Committee and fulfill all responsibilities to present pertinent information to the 
Ethics Committee responsible for the ethical issues of this study. 
I also agree to report all information or data in accordance with the 
protocol, and in particular, I agree to report any serious or non-serious adverse 
events related or not to the study medication. 
 
 
 
Signature - Principal Investigator  
 
Signature Date  
(dd/mm/yyyy) 
 
 
 
 
 
 
Name and position –  
Principal Investigator (printed) 
 
 
 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
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III.Description of the professionals and institutions involved in the research 
 
A. Research Center 
AZIDUS BRASIL PESQUISA CIENTÍFICA E DESENVOLVIMENTO LTDA. 
Rua General Osório, 507  
Valinhos/SP - ZIP Code: 13271-130 
Phone/Fax: (19) 3829-6160  
 
B. Sponsor 
CELLAVITA PESQUISA CIENTÍFICA LTDA 
Rua Martinho Leardine, 296 
Chácara Silvania  
Valinhos/ SP - ZIP Code: 13271-650 
 
E. Contact in case of Adverse Events  
Name  
 
MD Joyce Macedo- CRM: 134.721 
Position 
 
Principal Investigator 
Telephone       
(19) 98179-4142 
Email  
 
joyce.macedo@azidusbrasil.com.br 
 
F. Persons authorized to sign the protocol by Sponsor   
Name  
 
Cristiane Valverde 
Position 
 
Administrative Coordinator 
Email  
 
cristiane.valverde@Cellavitabrasil.com.br 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
Page 5 of 126 
IV.REVISION/VERSION CONTROL 
Status 
No. 
Date 
Reason for revision/version 
Version 
1.0 
21/12/2015 
Version after Sponsor's approval. 
Version 
1.0 
25/05/2016 
After the pending opinion (No. 1,521,528) issued by 
CONEP on May 17, 2016, the pending was answered 
and subsequently approved on 06/08/2016.  
Amendment 
1.0 
06/09/2017 
Changes to prevent the research participant from 
being exposed to unnecessary scans. Insertion of the 
6-month uniformization period before randomization / 
initiation of treatment and reduction of total treatment 
time with the possibility of continuing treatment in an 
extension study. There was the exchange of the 
principal investigator of the study due to the 
resignation of the former PI of the company. 
Amendment  
2.0 
29/09/2017 
Elucidate the activities that will be performed in each 
visit of the study as well as change the primary 
parameter, which instead of evaluating only the motor 
scale, will evaluate all domains of the UHDRS scale. 
Amendment  
3.0 
09/04/2018 
Restructuring of study visits and laboratory tests. 
Amendment  
4.0 
10/09/2018 
Correction some information existing in the previous 
version and improve the textual understanding of the 
activity to be performed during the study. 
Amendment  
5.0 
26/08/2019 
Clarify 
questions 
related 
to 
inclusion 
visits, 
uniformization and initiation of treatment that could 
generate doubt, in addition to textual review of motor 
and cognitive evaluation.  
Amendment  
6.0 
23/02/2021 
Exclusion of dosing of the prognostic biomarker NF-L 
(neurofilament protein) as an exploratory objective and 
alterations pertinent to the protocol procedures. 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
Page 6 of 126 
V.SYNOPSIS OF THE PROTOCOL 
 
Clinical Study Code  
 
 ADORE-DH 
Clinical Study Title 
EVALUATION OF THE DOSE-RESPONSE OF CELLAVITA HD 
INVESTIGATIONAL 
PRODUCT 
AFTER 
INTRAVENOUS 
APPLICATION 
IN 
PARTICIPANTS 
WITH 
HUNTINGTON'S 
DISEASE 
Status of the document 
Amendment 6 dated February 23, 2021. 
Population of the Clinical 
Study 
Participants of both genders, aged between 21 and 65 years, with 
laboratory diagnosis (genetic) of Huntington's disease and 
presenting the eligibility criteria determined for the study. 
Objective(s) for  
assessment of efficacy  
• Primary efficacy objective 
The primary objective of this clinical trial is to identify the dose of 
Cellavita-HD product that has the best clinical response. 
 
o Primary variable 
Verified through the Score of the UHDRS (Unified Huntington's 
Disease Rating Scale) of the baseline in relation to the end of 
treatment (domains that comprise the assessments: motor, 
cognitive, behavioral, functional capacity and independence). 
 
• Secondary efficacy objectives 
 The secondary objectives of the study are: 
a) Clinical neurological evaluation throughout the study; 
b) Overall assessment of Huntington's disease severity (CIBIS 
scale);  
c) BMI assessment;  
d) Assess the incidence of suicide attempts during treatment; 
e) Neurological evaluation by imaging. 
 
o Secondary variables 
a) Score of the UHDRS scale throughout the study (at each visit); 
b) Score of the CIBIS scale throughout treatment; 
c) Weight of the participant throughout the study;  
d) Score obtained in the suicide domain of the HAM-D scale 
during treatment; 
e) It will be assessed through the profiles obtained during the 
treatment of the following measures: 
• 
Cortical thickness; 
• 
Volume of the various brain structures, especially 
the core of the base, with special attention to the 
caudate; 
• 
Identifiable 
metabolic 
changes 
in 
proton 
spectroscopy. 
 
 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
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Objective for  
safety assessment 
The safety of the drug will be evaluated through the incidence and 
classification of adverse events occurring between treatments 
regarding type, frequency and intensity. 
Inclusion criteria 
a) 
Providing informed consent in writing, signed and dated; 
b) 
Participant of both genders aged ≥ 21 and ≤ 65 years*; 
c) 
Present confirmatory diagnostic report (PCR) of Huntington's 
disease with a number of CAG repeats on chromosome 4, greater 
than or equal to 40 and less than or equal to 50 (if the participant 
has not undergone the examination and/or if he/she does not have 
the report of the examination accessible, a new examination 
should be performed);  
d) 
Obtaining 5 points or more in the motor evaluation of the 
UHDRS (Unified Huntington's Disease Rating Scale) at the time of 
inclusion; 
e) 
Obtaining 8 to 11 points in the functional capacity of the 
UHDRS scale at the time of inclusion. 
*Note: The age of the participant will be considered on the day of the inclusion visit 
(V-3). 
Exclusion criteria 
a) Participant of the research who has participated in protocols of 
clinical studies in the last 12 (twelve) months, unless the 
researcher considers that there may be direct benefit to him/her 
(Resolution CNS 251, of August 7, 1997, item III, subitem J); 
b) Diagnosis of juvenile Huntington's disease*; 
c) Diagnosis of epilepsy; 
d) Diagnosis of major cognitive disorder; 
e) Decompensated active psychiatric disease; 
f) 
Current or past history of neoplasia; 
g) Current history of severe and uncontrolled gastrointestinal, 
hepatic, 
renal, 
endocrine, 
pulmonary, 
hematological, 
immunological, metabolic, or cardiovascular disease; 
h) Diagnosis of any active infection, be it viral, bacterial, fungal or 
caused by another pathogen; 
i) 
Participant who has contraindication to the tests performed in 
this study, such as having a pacemaker or surgical clip;  
j) Alcohol and drug abuse (previous diagnosis according to the 
criteria of the Diagnostic and Statistical Manual of Mental 
Disorders - DSM V); 
 k) Use of illicit drugs; 
 m) Present positive results in one of the serological tests: HIV 1 
and 2 (Anti-HIV-1.2), HTLV I and II, HBV (HBsAg, Anti-HBc), HCV 
(anti-HCV-Ab) and FTA-ABS (Treponema pallidum); 
 n) History of drug allergy, including contrasts for imaging, or 
bovine products; 
 o) In use or foresight of the use of immunosuppressive drugs or 
prohibited drugs (item 6.9) during the first three months after the 
first administration of the investigational product; 
p) Any clinical change that is interpreted by the Investigator 
physician as a risk to the inclusion of the participant in the study. 
 
*Note: The diagnosis of juvenile Huntington's will be defined by the presence of 60 
or more CAG repeats in the confirmatory diagnostic report for the disease and the 
appearance of characteristic signs and symptoms before the age of 21 (Nance, 
2001). 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
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Methodology 
The Clinical trial will be prospective, phase II, single-center, 
randomized (2:2:1), triple-blind, with two test-doses, placebo-
controlled. 
The study will include 35 participants. Initially, participants will be 
randomized in ratio 2 : 2 : 1 in groups G1: lower dose (1x106 
cells/weight range), G2: higher dose (2x 106 cells/weight range) or 
G3: placebo; i.e. of the 35 participants, 14 will be randomized to 
the lowest dose group, 14 for the highest dose group or 7 for the 
placebo group. The group receiving placebo is numerically smaller 
to prevent more people from not receiving treatment. 
Product Under 
Investigation 
Test 1: Cellavita-HD 
Dose: 1 x 106 cells/weight range per administration 
Pharmaceutical form: Liquid suspension of allogeneic cells. 
 
Test 2: Cellavita-HD 
Dose: 2 x 106 cells/weight range per administration 
Pharmaceutical form: Liquid suspension of allogeneic cells. 
Comparator Product  
• Placebo: test product base without allogeneic cells. 
Dosage 
Product dosage: both placebo and tests will be administered IV 
monthly until 3 doses (one cycle) are completed. There will be 3 
cycles throughout the study.  
Number of participants  
  35 participants. 
Duration of the  
Treatment 
The study will last approximately 14 months. (420 days) per 
participant.  
 
There are 15 scheduled visits, including:  
 
• 
Inclusion visit V-3 
• 
Uniformization visits (V-3, V-2 and V-1), 
• 
Visits to the administration of the investigational product 
(cycle 1 - Visits 0, 1 and 2; cycle 2 - Visits 4, 5 and 6; cycle 3 
- Visits 8, 9 and 10) 
• 
Follow-up visits (Visit 3, 7 and 11). 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
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VI.List of abbreviations and acronyms 
 
°C: Degree Celsius 
AEs: Adverse Events 
ANVISA: National Health Surveillance Agency 
ASC: Area Under the Curve 
BMI: Body Mass Index 
BP: Blood pressure 
CEP: Research Ethics Committee 
CFR: Code of Federal Standards 
CI: Confidence Interval 
CK: Creatine Kinase 
CKmB: Creatine Kinase mB 
Cmax: Maximum Concentration 
CNS: Central Nervous System 
CROR: Clinical Research Organization Representative  
DECH: graft-versus-host disease  
DMSO: Dimethyl Sulfoxide 
DRPLA: Dentatorubro-Palidoluisian Atrophy 
ECG: Cardiogram 
e-CRF: Clinical Record or Case Report Form 
EDC: Electronic Data Capture 
ELISA: Enzyme-Linked Immunosorbent Assay 
HD: Huntington's disease 
HR: Heart Rate 
FDA: Food and Drug Administration 
FES: Fatty Embolism Syndrome 
Gama-GT: Gamma glutamyl transferase 
GCP: Good Clinical Practices 
Hb: Hemoglobin 
HBV: Hepatitis B Virus 
HCV: Hepatitis C Virus 
HDL: High Density Lipoprotein 
HES: Hydroxyethyl Starches 
HGF: Hepatocyte Growth Factor 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica Ltda. 
Amendment 6 dated February 23, 2021. 
 
Confidential document 
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hIDPSC: Human Deciduous Tooth Pulp Stem Cells 
HIV: Human Immunodeficiency 
HSC: Hematopoietic Stem Cells 
Ht: Hematocrit 
HTLV: Human T Cells of Lymphotropic Virus 
HTT: Huntingtin Protein 
ICF: Informed Consent Form 
ICH: International Harmonization Conference 
IGF-1 and 2: Insulin-like Growth Factor 
ITT: Population of Analysis with Intent to Treat (Intention-to-Treat) 
IL: Interleukins 
LDL: Low Density Lipoprotein 
MSC: Mesenchymal Stem Cell 
Nanog: Transcription Factor and, Key Factor of Pluripotency 
NHC: National Health Council 
Oct-4: Octomer-4 Transcription Factor 
PCR: Polymerase Chain Reaction 
PP: Analysis Per Protocol  
SOPs: Standard Operating Procedures™ 
SAEs: Serious Adverse Events (Serious) 
SD: Standard deviation 
SDF: Stromal Derived Factor-1 
SSEA-3 and 4: Stage-Specific Embryonic Antigens 
TG: Triglycerides 
TGO: Oxalacetic Glutamic Transaminase 
TGP: Pyruvic Glutamic Transaminase  
TNF-α: Tumor Necrosis Factor alpha 
TRA 1-60, TRA 1-81: Tumor Recognition Antigens 
TRALI: Transfusion-Related Acute Lung Injury 
UHDRS: Unified Huntington's Disease Rating Scale 
USA: United States of America 
VEGF: Vascular Endothelial Growth Factor 
VLDL:  Very Low-Density Lipoprotein  
Vx: Visit Number x 
WHO: World Health Organization 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Cinetífica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
 
Confidential document 
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VII.Framework of study activities - Inclusion and Uniformization Period 
 
 
Activities 
Inclusion 
Uniformization 
V-3 
V-2 
V-1 
 
-37 to -1 days before V-
2 
 
Up to 30 + 7 days after 
V-3 
 
30 + 7 days after V-2 
Consent form (ICF) 
X 
 
 
Evaluation of inclusion/exclusion criteria 
X 
Xa 
Xa 
Medical evaluation: medical history, and 
physical examination/vital data 
X 
X 
X 
Demographic data (date of birth, gender and 
race) 
X 
 
 
Confirmation or performance of laboratory 
diagnosis of Huntington's disease 
X 
 
 
Evaluation of laboratory diagnosis of 
Huntington's disease, if applicable 
 
Xb 
 
Blood and urine collection for laboratory 
inclusion tests 
X 
 
 
Evaluation of laboratory blood and urine tests 
 
X 
 
Pregnancy urinary test for women 
X 
X 
X 
Blood collection for serology examination 
X 
 
 
Evaluation of the serology examination 
 
X 
 
ECG performance 
X 
 
 
Evaluation of ECG result 
 
X 
 
Performance of CNS MRI  
 
X 
 
 
Assessment of the CNS MRI result 
 
X 
 
UHDRS Scale 
X 
X 
X 
CIBIS Scale 
X 
X 
X 
Hamilton Depression Assessment Scale  
(HAM-D) 
X 
X 
X 
Activities 
Inclusion/uniformization 
Uniformization 
V-3 
V-2 
V-1 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Cinetífica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
 
Confidential document 
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a Items "d" and "e" of the inclusion criteria will be evaluated only at the inclusion visit (V-3) due to the natural fluctuation of the 
disease 
b For participants who need to carry out the laboratory diagnosis of Huntington's disease, the test will be performed at V-3 and 
evaluated at V-2 
 
-37 to -1 days before V-
2 
 
Up to 30 + 7 days after 
V-3 
 
30 + 7 days after V-2 
Concomitant/prior medication registration 
X 
X 
X 
Evaluation of adverse events 
X 
X 
X 
Assessment of pregnancy risk and 
dispensation of contraceptive method, if 
applicable. 
X 
X 
X 
General guidelines 
X 
X 
X 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Cinetífica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
 
Confidential document 
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VII. Framework of study activities - Treatment and Follow-up Period 
 
 
Activities 
V0 
Start of 
treatment - 
Up to 30 
days after 
V-1 
V1 
 
30+5 
days 
after V0 
V2 
 
60+5 
days 
after V0 
 
V3 
 
90+5 
days 
after V0 
V4 
 
120+5 
days 
after V0 
V5 
 
150+5 
days 
after V0 
V6 
 
180+5 
days 
after V0 
V7 
 
210+5 
days 
after V0 
V8 
 
240+5 
days 
after V0 
V9 
 
270+5 
days 
after V0 
V11 
 
300+5 
days 
after V0 
V11c 
 
330+5 
days after 
V0 
1st adm. 
Cycle 1 
2nd adm. 
Cycle 1 
3rd adm. 
Cycle 1 
F-up. 
1st adm. 
Cycle 2 
2nd adm. 
Cycle 2 
3rd adm. 
Cycle 2 
F-up. 
1st adm. 
Cycle 3 
2nd adm. 
Cycle 3 
3rd adm. 
Cycle 3 
Final 
Evaluation of inclusion criteria/ 
Exclusion (except criteria "d" and 
"e") 
X 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of discontinuation criteria 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical evaluation: medical history 
and physical examination/vital data  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
Intravenous administration of 
Cellavita-HD or placebo 
(hospitalization for a period prior to 
administration and for another 06 
hours) 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
 
Blood and urine collection for 
laboratory tests 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Evaluation of laboratory test results 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Pregnancy urinary test for women  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection for serology 
 
 
 
 
 
 
 
 
 
 
 
X 
Evaluation of serology result 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG performance 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Evaluation of ECG result 
 
 
 
 
X 
 
 
 
X 
 
 
X 
ECG monitoring  
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
UHDRS and HAM-D scale and 
CIBIS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI for CNS evaluation 
 
 
 
 
 
 
 
 
 
 
 
X 
Evaluation of CNS MRI result 
 
 
 
 
 
 
 
 
 
 
 
X 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Cinetífica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
 
Confidential document 
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Activities 
V0 
Start of 
treatment - 
Up to 30 
days after 
V-1 
V1 
 
30+5 
days 
after V0 
V2 
 
60+5 
days 
after V0 
 
V3 
 
90+5 
days 
after V0 
V4 
 
120+5 
days 
after V0 
V5 
 
150+5 
days 
after V0 
V6 
 
180+5 
days 
after V0 
V7 
 
210+5 
days 
after V0 
V8 
 
240+5 
days 
after V0 
V9 
 
270+5 
days 
after V0 
V11 
 
300+5 
days 
after V0 
V11c 
 
330+5 
days after 
V0 
1st adm. 
Cycle 1 
2nd adm. 
Cycle 1 
3rd adm. 
Cycle 1 
F-up. 
1st adm. 
Cycle 2 
2nd adm. 
Cycle 2 
3rd adm. 
Cycle 2 
F-up. 
1st adm. 
Cycle 3 
2nd adm. 
Cycle 3 
3rd adm. 
Cycle 3 
Final 
Concomitant medication registration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of pregnancy risk and 
dispensation of contraceptive 
method, if applicable. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
General guidelines 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensation from the study 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a Hospitalization for 06 hours: all procedures provided for in the protocol should be performed at the times determined, including evaluation of vital signs, clinical examination and ECG. The length of 
stay can be extended at the discretion of the principal investigator. 
b In this visit, because it is the last visit of the study, there will be no dispensation of contraceptive method, only assessment of the risk of pregnancy. 
c If any examination performed on this visit presents any clinically significant abnormality, the research participants will be invited to perform an extraordinary visit.   
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
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Summary 
 
1. 
INTRODUCTION ........................................................................................................................ 19 
1.1. 
Tooth pulp as a source of mesenchymal stem cells ................................................................. 19 
1.2. 
Characterization of the investigational product ...................................................................... 20 
1.3. 
Therapeutic target: Huntington's disease (HD)........................................................................ 21 
1.3.1. Pharmacological approach ....................................................................................................... 26 
1.3.2. Non-pharmacological approach ............................................................................................... 26 
1.3.3. Use of cell therapy in Huntington's disease ............................................................................. 27 
2. 
JUSTIFICATION FOR CARRYING OUT THE STUDY ..................................................................... 29 
3. 
OBJECTIVES............................................................................................................................... 32 
3.1. 
Primary objective of effectiveness ........................................................................................... 32 
3.2. 
Secondary objectives of effectiveness ..................................................................................... 32 
3.3. 
Safety objective ........................................................................................................................ 33 
3.4. 
Study hypothesis ...................................................................................................................... 33 
4. 
STUDY OVERVIEW .................................................................................................................... 34 
4.1. 
Study design ............................................................................................................................. 34 
4.2. 
Phase ........................................................................................................................................ 34 
4.3. 
Possible treatment groups ....................................................................................................... 34 
4.4. 
Duration of the study ............................................................................................................... 34 
4.5. 
Visit schedules .......................................................................................................................... 34 
4.6. 
Panoramic description of the study - Study plan ..................................................................... 36 
5. 
STUDY POPULATION ................................................................................................................. 41 
5.1. 
Population description ............................................................................................................. 41 
5.2. 
Inclusion and exclusion criteria ................................................................................................ 41 
5.2.1. Inclusion criteria ....................................................................................................................... 41 
5.2.2. Exclusion criterion .................................................................................................................... 41 
5.2.3. Discontinuation criteria (interruption) of treatment with the investigational product: ......... 42 
5.3. 
Selection failure ....................................................................................................................... 43 
5.5. 
Follow-up of research participants whose continuation in this study is interrupted .............. 44 
5.6. 
Recruitment strategies ............................................................................................................. 44 
6. 
STUDY TREATMENT .................................................................................................................. 45 
6.1. 
Identification of the investigational product ........................................................................... 45 
6.2. 
Treatment groups .................................................................................................................... 45 

Clinical Protocol: ADORE-DH 
 
Sponsor: Cellavita Pesquisa Científica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
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6.3. 
Dosage ...................................................................................................................................... 45 
6.4. 
Treatment allocation / Concealment of allocation .................................................................. 46 
6.5. 
Study blinding / Procedure for blind breakage ........................................................................ 46 
6.6. 
Packaging and labelling ............................................................................................................ 47 
6.7. 
Storage and stability ................................................................................................................. 48 
6.8. 
Chain of custody ....................................................................................................................... 48 
6.9. 
Concomitant medicinal products prohibited during the study ................................................ 49 
7. 
SCHEDULE OF VISITS AND PROCEDURES OF THE STUDY ......................................................... 50 
7.1. 
Procedure for entry of Participants ......................................................................................... 50 
7.1.1. Informed Consent Form (ICF) ................................................................................................... 50 
7.1.2. Preserving the identity of research participants ...................................................................... 50 
7.1.3. Acceptable contraceptive methods ......................................................................................... 51 
7.1.4. Exams performed for inclusion of study participants .............................................................. 51 
7.2. 
Study-specific evaluations and procedures ............................................................................. 52 
7.2.1. Laboratory diagnosis for Huntington's disease (PCR) .............................................................. 52 
7.2.2. Clinical evaluation: demographic data, medical history and physical examination ................ 52 
7.2.3. Laboratory tests and serology .................................................................................................. 54 
7.2.4. Cardiogram ............................................................................................................................... 55 
7.2.5. Application of the UHDRS Scale (Unified Huntington's Disease Rating Scale) ......................... 56 
7.2.6. Application of the Hamilton Depression Assessment Scale (HAM-D) ..................................... 59 
7.2.7. CIBIS Scale Application – Clinician Interview Based Impression .............................................. 60 
7.2.8. BMI Assessment (Body Mass Index) ........................................................................................ 60 
7.2.9. Evaluation of the CNS by magnetic resonance imaging of the brain ....................................... 61 
7.3. 
Plan of visits and activities to be carried out at each visit ....................................................... 62 
7.3.1. Visit of inclusion and beginning of uniformization .................................................................. 62 
7.3.2. Uniformization period .............................................................................................................. 63 
7.3.3. Treatment and Follow-up Visits ............................................................................................... 64 
7.4. 
Extraordinary Visits .................................................................................................................. 71 
7.5. 
Adherence ................................................................................................................................ 71 
8. 
STATISTICAL PROCEDURES ....................................................................................................... 72 
8.1. 
Sample size determination ....................................................................................................... 72 
8.2. 
Analysis Populations................................................................................................................. 72 
8.3. 
Measurement of the primary variable ..................................................................................... 73 
8.4. 
Measurement of secondary variables ...................................................................................... 74 
8.5. 
Measurement of the Safety Variable ....................................................................................... 75 

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8.6. 
Study hypotheses ..................................................................................................................... 76 
8.6.1. Primary Hypothesis .................................................................................................................. 76 
8.6.2. Secondary hypotheses ............................................................................................................. 76 
8.7. 
Statistical analysis .................................................................................................................... 76 
8.7.1.1. Analysis of demographic and baseline data ............................................................................. 76 
8.7.1.1.1. 
Hypothesis analysis 1 ........................................................................................................ 76 
8.7.1.1.2. 
Analysis of secondary hypotheses .................................................................................... 76 
8.7.1.1.3. 
Analysis of the safety hypothesis ..................................................................................... 77 
8.7.1.1.4. 
Exploratory analyses ......................................................................................................... 77 
8.8. 
Data management plan summary ............................................................................................ 77 
8.8.1. Deviations from the Original Statistical Plan............................................................................ 77 
8.8.2. Record of analyzed parameters ............................................................................................... 77 
8.8.3. Data Capture - Clinical Record (CRF) ........................................................................................ 78 
8.8.4. Data validation – Plan of Queries ............................................................................................. 78 
8.8.5. Database cleanup and freezing ................................................................................................ 78 
8.9. 
Handling Missing or Invalid Data.............................................................................................. 79 
8.10. 
Interim analyses ....................................................................................................................... 79 
9.1. 
Adverse events ......................................................................................................................... 80 
9.1.1. Serious adverse events ............................................................................................................ 80 
9.1.2. Classification of adverse events according to expectation ...................................................... 81 
9.1.3. Classification of adverse events in terms of intensity .............................................................. 82 
9.1.4. Causality categories: WHO-UMC System ................................................................................. 82 
9.2. 
Contact with the Sponsor ......................................................................................................... 83 
9.3. 
Follow-up of reports of adverse events ................................................................................... 84 
9.4. 
Reports of pregnancy occurrence with direct or indirect exposure to the investigational 
product of the study .............................................................................................................................. 84 
9.4.1. Gestational follow-up ............................................................................................................... 84 
9.4.2. Pregnancy with direct or indirect exposure to the investigational product under study ........ 85 
9.4.3. Notification to the Research Ethics Committee (CEP) ............................................................. 85 
9.4.4. Consistency of information notified by Research Center to the Sponsor ............................... 85 
9.5. 
Expected adverse events with cell therapy .............................................................................. 85 
9.6. 
Record of safety parameters .................................................................................................... 87 
9.6.1. Suspension of administration of the investigational product .................................................. 87 
9.6.2. Study Interruption/Suspension ................................................................................................ 88 
9.7. 
Providing data and tracking of participants ............................................................................. 89 

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9.7.1. Contact with the Sponsor ......................................................................................................... 89 
10. 
ETHICAL AND REGULATORY CONSIDERATIONS ....................................................................... 90 
10.1. 
Declaration of the Americas and Regulation ........................................................................... 90 
10.2. 
Belmonte Communication ....................................................................................................... 90 
10.3. 
Informed Consent Form (ICF) and Image Authorization Term ................................................ 90 
10.4. 
Risks and benefits ..................................................................................................................... 91 
10.5. 
Preserving the identity of research participants ...................................................................... 92 
10.6. 
Post-study drug supply ............................................................................................................. 92 
10.7. 
Declaration of interest ............................................................................................................. 93 
10.8. 
Ethics and publication policy .................................................................................................... 93 
11. 
PROTOCOL CHANGES ............................................................................................................... 94 
11.1. 
Amendments ............................................................................................................................ 94 
11.2. 
Amendment submission .......................................................................................................... 94 
11.3. 
Deviations and protocol violations .......................................................................................... 94 
12. 
SUSPENSION, CLOSURE AND COMPLETION OF THE STUDY ..................................................... 96 
13. 
QUALITY CONTROL ................................................................................................................... 97 
14. 
DATA CONTROL AND RECORD MAINTENANCE ........................................................................ 98 
14.1. 
Investigator .............................................................................................................................. 98 
14.2. 
Sponsor .................................................................................................................................... 98 
15. 
REFERENCES ............................................................................................................................. 99 
16. 
ATTACHMENTS ....................................................................................................................... 107 
 
 
 

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1. 
INTRODUCTION 
According to ANVISA definition, cell therapy aims to restore the function of 
an organ or tissue of the human body, through the transplantation of cells that have 
differentiation capacity. Cell therapy with stem cells is considered an example of 
regenerative medicine and is currently in the world stage, as it may represent the 
improvement or maintenance of quality of life for patients affected by pathologies that 
are extremely debilitating and do not have a cure so far, such as degenerative 
diseases. In Brazil, the use of stem cells for therapeutic purposes has also been the 
target of research, however, compared to other countries, it is currently in the early 
stages (Pereira & Queiroz, 2012, ANVISA, 2015). 
The term "Stem cell" was proposed by the Russian histologist Alexander 
Maksimov in 1908 for scientific use. By definition, stem cells are primitive and 
undifferentiated cells, which have the ability to replicate indefinitely and/or 
differentiate into several cell types (Kim & Vellis, 2009; de Souza et al., 2013; Zuttion 
et al., 2013). Among the tissues known to have stem cells, the bone marrow was the 
most studied, as a source of both hematopoietic stem cells (HSC), which classically 
give rise to all blood lineage, as well as mesenchymall stem cells (MSC), which give 
rise to various connective tissues and other non-mesodermal cell types such as 
neural cells and hepatocytes (Bydlowski et al., 2009; Kim & Vellis, 2009; de Souza et 
al., 2013; Zuttion et al., 2013). 
 
1.1. 
Tooth pulp as a source of mesenchymal stem cells 
Mesenchymal stem cells are found not only in the bone marrow, but also 
in the umbilical cord, tooth pulp and fat, and are responsible for tissue regeneration in 
cases of injury during life. Mesenchymal cells secrete a variety of biomolecules such 
as cytokines, which have trophic activity and are capable of promoting a regenerative 
microenvironment, in addition to other molecules that contribute to tissue 
reconstruction, such as immunomodulatory mediators. In general, mesenchymal cells 
can reduce chronic inflammation, inhibit apoptosis, stimulate mitosis of tissue-intrinsic 
progenitors, stimulate angiogenesis and neurogenesis, and reduce tissue destruction 
due to oxidative stress, i.e., they are capable of improving the injured 
microenvironment and promoting tissue remodeling (Aleynik et al., 2014; Kerkis et 
al., 2015; Kerkis & Caplan, 2012; Kim & Cho, 2013). 

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Several studies have shown that the pulp of deciduous teeth (milk tooth) is 
a tissue rich in mesenchymal stem cells and that these cells have high differentiation 
capacity in several cell lines, in addition to rapid proliferation, high clonogenic 
capacity and excellent expansion in vitro, and can be kept in culture for a long period 
of time. In addition, the removal of these cells does not present any ethical restriction, 
since deciduous teeth are discarded after a natural process of primary resorption of 
the tooth root (exfoliation) and, if necessary, the technique of excision of the tooth, is 
considered simple and minimally invasive (Kerkis et al., 2015; Kerkis & Caplan, 
2012). 
 
1.2. 
Characterization of the investigational product  
The investigational product object of study in this protocol, called Cellavita-
HD is a biotechnological product developed by a group of researchers in stem cells 
of the Butantan Institute led by Prof. Dr. Irina Kerkis. It has been researched and 
validated for years and today is characterized as a product originating from human 
deciduous tooth pulp stem cells (Human Immature Dental Pulp Stem Cells – or in 
abbreviated form, hIDPSC). The cells that are present in the Cellavita-HD product 
correspond to the population of somatic/adult stem cells similar to mesenchymal 
stem cells (MSC) (Kerkis et al., 2015; Kerkis & Caplan, 2012). This technology was 
patented by the research group (Prof. Dr. Irina Kerkis) and the Butantan Institute 
(Application number CT/IB2014/059850). In 2014, this patent was licensed by a 
biotechnology company, 100% Brazilian Start-up, called Cellavita Pesquisa Científica 
Ltda. 
This biotechnology developed by the group allows the origin from a single 
tooth pulp a large amount of stem cells, which allows the clinical investigation of 
possible beneficial properties of these cells in patients with neurodegenerative 
diseases (considering the ability of these cells to differentiate into neurons).  
In 2006, Dr. Irina Kerkis et al. isolated hIDPSC cells from dental pulp 
following the pulp tissue explant technique (procedure used for the isolation of neural 
crest stem cells), under cultivation conditions similar to those used for embryonic 
stem cells (Kerkis et al., 2006; Kerkis & Caplan, 2012; Kerkis et al., 2015). Due to the 
characteristics related to their embryogenesis, these cells present promising and 
diversified therapeutic possibilities resulting from their rapid proliferation, high 
differentiation capacity in several cell lines (multipotential properties), in addition to 

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the ability to acquire the phenotype of another cell of a different tissue or organ 
(plasticity) (Kerkis et al., 2015; Kerkis & Caplan, 2012).  
Immunocytochemical studies have shown that these cells express some 
markers of human embryonic stem cells such as Oct-4 (Oct-4 transcription factor), 
Nanog (transcription factor and key factor of pluripotency), SSEA-3 and 4 (stage-
specific embryonic antigens), TRA 1-60, TRA 1-81 (tumor recognition antigens), but 
also mesenchymal stem cell markers such as CD105 (SH2), CD73 (SH3 and SH4), 
CD13 and CD31, which were observed in approximately 97% of the cells. No 
hematopoietic markers were found (Kerkis et al., 2006; Kerkis & Caplan, 2012; 
Kerkis et al., 2015).  
To date, the Cellavita-HD investigational product has not presented any 
clinical or experimental evidence that could compromise the safety of the use of this 
therapy, such as tumor formation or risk of immune rejection. A relevant 
characteristic of this type of cell is its ability to migrate to pathological sites, a 
mechanism called pathotropism, in addition to its property of crossing the blood brain 
barrier and reaching the central nervous system (CNS) (Aleynik, et. al., 2014; Kerkis 
et al., 2015; Kerkis & Caplan, 2012). In addition, the process of in vitro expansion 
and proliferation of these cells is standardized to be cryopreserved in a Cell Bank 
(Master Cell Bank) and used in future clinical applications of cell therapy (Almeida, 
et. al., 2011; Kerkis & Caplan, 2012). 
First, Huntington's disease was established as a therapeutic target of the 
Cellavita-HD investigational product. Next, the main aspects of this pathology are 
described.  
 
1.3. 
Therapeutic target: Huntington's disease (HD) 
Huntington's disease (HD) is a fatal, genetic, highly debilitating and 
progressive neurodegenerative disorder characterized by the following clinical signs 
and symptoms: cognitive, motor and psychiatric dysfunction. Usually, the onset of 
symptoms of the disease occurs between 25 and 45 years of age (ranging from 3-70 
years). Once started, cognitive-behavioral symptoms and engines progress 
inexorably until they result in a fatal outcome. The most striking sign of the disease is 
the presence of involuntary movements, called choreic movements, which are 
continuous, brief, random and result in contractions of the orofacial muscle and limbs 
(Ross et al., 2014; Nuzzo et al., 2014). Emotional changes and behavioral changes 

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that result in anxiety and depression, although frequent, do not occur uniformly 
among patients, as motor and cognitive alterations occur (Ross et al., 2014). 
Several factors alter the overall prevalence of the disease, such as: 
different ethnicities, geography, migration patterns and location. The disease has a 
global prevalence of about 5.7 cases per 100,000 people in the Western world, and 
the incidence is more prevalent in descendants of Western Europe, North and South 
America and Australia, and rare in Africans and Asians (Olanow and Schapira, 2012; 
Gonçalves, 2013). HD is an autosomal dominant genetic disorder caused by a 
mutation in the huntingtin protein gene (HTT), located on the short arm of 
chromosome 4 (location 4p 16.3). This genetic mutation causes increased repetition 
of the CAG trinucleotide sequence (responsible for encoding the glutamine). This 
abnormal repetition expanded produces a protein with a long chain of glutamine, 
known as polyglutamine or PolyQ, in the N-terminal region of exon 1 of the gene, 
which constitutes the abnormal huntingtin protein (Figure 1) (Squitieri et al., 2006; 
Gonçalves, 2013; Ross et al., 2014; Nuzzo et al., 2014). HD is one of the 9 PoliQ 
disorders, which additionally include spinocerebellar ataxias (ACE type 1, 2, 3, 6, 7 
and 17), bulbospinal muscular atrophy and dentorubro-palidoluisian atrophy 
(DRPLA), and among these, HD is the most prevalent (Schols et al, 2004). 
 

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Figure  1. Illustration demonstrating how the Huntingtin gene mutation (HTT) produces increased 
repetitions of the CAG sequence, generating the abnormal huntingtin protein that causes neuronal 
degeneration.  
Source:http://www.eurostemcell.org/factsheet/Huntington%E2%80%99s-disease-how-could-stem-
cells-help 
 
Although the first more detailed report of the disease occurred in 1872 by 
physician George Huntington, it was in the year of 1983 that the mutation of the gene 
HTT which causes the disease was localized and, in 1993, it was isolated by a group 
of researchers (Huntington's Disease Collaborative Research Group) who identified 
the mutation precisely on chromosome 4 in the IT15 part (Zuccato et al., 2010; 
Finkbeiner, 2011; Colle, 2012; Gonçalves, 2013). The gene HTT has a large DNA 
sequence (180 kb) consisting of 67 exons (Ambrose et al., 1994) and its sequence 
differs from any gene identified earlier (The Huntington's Disease Collaborative 
Research Group, 1993). 
Individuals not affected by the disease who have normal huntingtin protein 
have on average a sequence of 19 repetitions of glutamine. On the other hand, HD 
patients have the number of CAG repeats in the HTT above 35 (Kremer et al., 1994; 
Hogarth, 2013). According to the number of repetitions that the mutation causes, 
different phenotypes of the disease may be observed, especially with regard to the 
age of onset of clinical manifestations. In this way, with CAG repeats of 36 to 39 
(gray zone – incomplete penetrance) the patient may remain asymptomatic for many 
years and the onset of symptoms occur later, with slower progression (Rubinsztein et 

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al., 1996; Quarrell et al., 2007). However, higher repetitions of the PoliQ sequence 
(mainly above 60), may result in more severe conditions of the disease in which 
symptoms onset earlier (before 20 years of age) and progress faster than in patients 
with fewer repetitions (Telenius et al., 1993). These more serious conditions (called 
juvenile HD) represent about 7% of all cases of HD and, because having a rapid 
progression can lead these patients to death in about 11 years (Foroud et al., 1999; 
Gonçalves, 2013).  
Despite being a hereditary and autosomal dominant disease, sporadic 
cases of HD have been reported in patients with asymptomatic parents who have 30-
35 polyQ repeats (De Rooij et al., 1993; Goldberg et al., 1993; Hendricks et al., 
2009). This fact corroborates the information found in the review by Gil-Mohapel & 
Rego (2011) and in Hogarth's article (2013), in which both discuss and describe the 
risk of HD transmission, according to the amount of CAG repetitions that the 
individual has. According to these authors, individuals who have 28-35 CAG repeats 
will not manifest the disease, however their descendants may have an increased risk 
of developing the disease if mutations occur in this gene (Gil-Mohapel and Rego, 
2011; Hogarth, 2013). Figure 2 classifies the risk of transmission of the disease 
according to the number of CAG repetitions that the individual has. 
 
 
Figure  2.Classification of the risk of transmission of the disease according to the number of 
repetitions of the CAG sequence in individuals. CAG = less than 27 → Normal Result: there is no risk 
to develop the disease and transmit to descendants. CAG = 27 - 35 → the Gray Zone: no risk to 
develop the disease, but at risk of transmitting to the descendants. CAG = 36-39 → Gray zone: risk of 
manifesting the disease in adulthood and risk of transmission to descendants. CAG = greater than 40 

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→ Abnormal Outcome: manifestation of the disease at some point in life and transmission to 
descendants.  Source: Hogarth, 2013. 
 
The function of normal huntingtin protein (Htt) is not well established in 
humans, however it is suggested that this protein presents interaction with several 
proteins involved in transcription processes, cell signaling and intracellular transport. 
In addition, this protein has a vital function in embryonic development, a data 
collected from studies carried out with genetically manipulated animals to develop 
HD, in which they showed that the absence of Htt is directly related to the death of 
the embryo (Gonçalves, 2013).  
Similarly, although the mechanism by which abnormal huntingtin protein 
acts in tissues is not fully known, it is known that it is potentially toxic to cells, 
affecting the middle spinous neurons in the CNS, specifically in the region of the 
Striatum at the onset of the disease and then in other areas of the brain such as 
thalamus and the cerebral cortex, as the disease progresses (Mink, 1996; 
Silverthorn, 2003; Vonsatteland Di Figlia, 1998; Gil-Mohapel and Rego, 2011).  
The middle spinous neurons of the Striatum have inhibitory function over 
the other areas with which it communicates through gamma-aminobutyric acid 
(GABA) neurotransmitters and the co-transmitters dinorphine, Encephalin or 
substance P. Thus, the loss of the inhibitory effect caused by the death of the middle 
spinous neurons results in the loss of thalamus inhibition, which leads to increased 
activation of the direct circuit of the basal ganglia and consequent exacerbation of 
nerve impulses to the motor regions of the body, limbs and eyes, causing the 
undesirable choreic movements characteristic of HD (Mink, 1996; Wolf, 2009; Gil-
Mohapel and Rego, 2011). 
With the progression of the disease, there is an increase in cell death in 
other areas of the brain and as a result, patients with HD present emotional, cognitive 
and motivational difficulties, in addition to motor complications, behavioral and mood 
changes, loss weight, irritability, anxiety and depression (Foroud et al., 1999; 
Vonsattel and DiFiglia, 1998). Cognitively, there is a deficit on executive functions 
(Walker, 2007). With the progression of the disease, patients develop difficulties in 
coordination, including speech, swallowing and walking (Foroud et al., 1999). 
Disease-associated mortality is often related to complications such as pneumonia 
and heart disease (Sorensen and Fenger, 1992; Zuccato et al., 2010). 

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Huntington's disease has no cure and there are no medicines to date that 
can stop or reverse its progression. However, there are treatments with 
pharmacological and non-pharmacological approaches that only mitigate the 
symptoms presented by patients (symptomatic treatments). 
 
1.3.1. Pharmacological approach 
The medications most commonly prescribed for these patients include 
antipsychotics, anxiolytics, antidepressants, mood stabilizers and, in patients with 
juvenile HD, anticonvulsants. Dopamine-blocking agents, such as tetrabenazine, 
which has been approved by the United States of America (USA), can control the 
symptoms of chorea (Hayden et al., 2009; Wang et al., 2010). The same 
antipsychotic medications such as haloperidol, clozapine, chlorpromazine and 
olanzapine are prescribed to reduce chorea as they have dopamine antagonistic 
action and, additionally, the benefit of controlling the behavioral and/or psychotic 
characteristics that HD patients may present (Jankovic, 2009; Phillips et al., 2008). 
To 
deal 
with 
symptoms 
of 
depression, 
suicidal 
thoughts 
and 
impulsiveness, Antidepressant medications (fluoxetine, escitalopram, sertraline, 
paroxetine and venlafaxine) are often prescribed for HD patients. In addition, 
anxiolytic medicines such as diazepam, benzodiazepines (Clonazepam, Alprazolam), 
paroxetine and venlafaxine are indicated to calm patients and mitigate anxiety 
symptoms associated with the disease (Phillips et al., 2008; Kaplan and Stockwell, 
2012). 
For 
mood 
stabilization, 
drugs 
such 
as 
lithium, 
valproate 
and 
carbamazepine can be prescribed to patients (Bonelli and Wenning, 2006). There are 
a lot of medications that can be used to control HD, however, many of these cause 
adverse effects that can worsen the patient's functionality and quality of life. To date, 
there is no adequate treatment for the inevitable cognitive and motor decline 
observed in HD progression (Olanow & Schapira, 2012). 
 
1.3.2. Non-pharmacological approach 
Physical and occupational therapies can promote improved motor 
coordination in the early stages of the disease and exercises can strengthen muscles 
and improve balance and posture. Psychiatric therapy can help reduce anxiety, 
depression, stress, as well as help cope with the changes associated with the 

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disease. Additionally, decreased stress and anxiety can help in the control of chorea. 
Speech therapists can work with HD patients assisting in communication and 
swallowing problems (Bilney et al., 2003). 
 
1.3.3. Use of cell therapy in Huntington's disease 
Cell therapy has been actively researched as a therapeutic alternative to 
modify the course of Huntington's disease, especially regarding neurodegeneration 
and selective neuronal loss of middle spinous neurons, which occurs in the striated 
body and deeper layers of the brain. Some studies have been published using 
striated brain tissue transplantation (Striatum) of a human fetus and an improvement 
in motor and cognitive performance in HD patients was observed, along with 
reduction of cerebral neuronal injury. However, the effects were considered 
temporary because the follow-up studies, who followed these participants 3 to 10 
years after transplantation, showed that the therapy is safe, but its effects were not 
sustained (Bachoud-Lévi et al., 2000; Bachoud-Lévi et al., 2006; Barker et al., 2013; 
Fink et al., 2015). Additionally, animal studies have shown a positive effect on 
neuronal dysfunction when muscle cell transplantation of the striatum (Nakao & 
Itakura, 2000) was performed and demonstrated that the graft progressively 
integrated into the degenerate striated body in a transgenic model for HD. However, 
complete recovery has not been reported in any of these studies (Dunnett et al., 
1998; Kim & Vellis, 2009). 
An important limiting factor for the transplantation of fetal cells of the 
striatum is the difficulty in providing sufficient amount of cells and embryonic striated 
tissue, in addition to the ethical problems associated with the use of embryonic 
human tissues. In this sense, the stem cells grown in vitro and expanded neural or 
mesenchymal stem cell precursors are of great clinical interest (Kim & Vellis, 2009: 
Kerkis et al., 2015a). Recent studies also indicate that the regenerative effect caused 
by cell therapy actually occurs through secretory molecules in addition to cell 
replacement, such as paracrine communication. In this sense, mesenchymal stem 
cells stand out in relation to other cell types due to their ability to secretion of a 
variety of growth factors, cytokines and chemokines that regulate their biology in an 
autocrine/paracrine way and are able to interact with the microenvironment around 
them, creating a neuroprotective microenvironment. Growth factors such as VEGF 
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(Insulin-like Growth Factor) and SDF (Stromal derived factor-1) secreted by 
mesenchymal stem cells are important for neuronal survival, neurogenesis, 
migration, differentiation and mitochondrial activation (Kerkis et al., 2015a; Aleynik, 
et. al., 2014; Kerkis et al., 2015; Kerkis & Caplan, 2012).  
Thus, mesenchymal stem cells have two main therapeutic mechanisms, 
which are: (1) secretion of a variety of growth factors and signaling molecules that 
potentially increase the overall regenerative capacity of the tissue, as well as its 
immunomodulation, by creating a microenvironment capable of regulating intrinsic 
cell proliferation and promoting neuroprotection and/or, (2) replacement or repair of 
neurons. These positive effects combined with the ability of mesenchymal cells to 
migrate to the injured site could potentially function as a neuroprotective therapy and 
inhibit disease progression or even, in the best case, be able to recover the injured 
area, even partially, reducing disease-related symptoms (Kerkis et al.,2015a; Aleynik, 
et. al., 2014; Kerkis et al., 2015; Kerkis & Caplan, 2012.; Fink et al., 2015; Kim & 
Cho, 2013).  
Based on this, it is assumed that, after crossing the blood brain barrier, the 
Cellavita-HD investigational product would be able to secrete neurotropic and 
immunomodulatory factors and act in places where there is tissue damage caused by 
Huntington's disease, in order to alleviate neurological damage and restore even 
partially degenerated tissue. Therefore, cell therapy with Cellavita-HD in Huntington's 
disease has as its ultimate goal the reduction of neuronal loss and stimulation of 
neurogenesis, both endogenous and newly transplanted cells, activating a 
neuroprotective environment that is able to integrate new cells and replace dead 
neural cells or in the process of apoptosis.  
Some authors believe that although cell therapy with stem cells, 
embryonic or neural, shows a beneficial effect both experimental and clinical, they do 
not represent the effective and definitive cure for the natural progression of 
Huntington's disease, due to the genetic nature of it and the fact that the mutant 
huntingtin protein can cross the cell membranes and propagate in the new 
transplanted cells. Therefore, cell therapy would only be able to delay the onset or 
course of the pathology, which, given the devastating nature of the disease, would 
already represent a major advance for these patients (Fink et al., 2015).  

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2. JUSTIFICATION FOR CARRYING OUT THE STUDY  
Huntington's disease (HD) is a genetic neurodegenerative disease 
characterized by choreic movements, cognitive impairment, and psychiatric 
disorders. Several pharmacological treatments are used to improve or mitigate the 
symptoms of the disease, however, these do not promote the cure of the condition 
and do not alter its natural evolution, so that, to date, there is no adequate treatment 
for the inevitable cognitive-behavioral decline and motor observed in HD. Disease-
modifying or neuroprotective therapy that decreases disease progression represents 
the largest and most important clinical need not yet met in HD (Olanow & Schapira, 
2012; Kim & Vellis, 2009). 
Stem cell therapy is currently prominent on the world stage and represents 
a new possibility of treatment, mainly for neurological diseases and CNS injuries, 
partly due to its inherent ability to repair. Mesenchymal stem cells are of particular 
clinical interest, due to their ability to migrate to sites with injury and to release 
beneficial neurotrophic factors, with consequent promotion of a restorative 
microenvironment. While embryonic stem cells presented some technical and ethical 
problems, as well as limited clinical benefits, mesenchymal stem cell therapies 
proved clinically beneficial, safe and without ethical problems involved, as they are 
derived from adult non-embryogenic tissue (Fink et al., 2015: Kim & Cho, 2013). 
According to the recent review conducted by Fink et al. (published in August 2015), 
the historical profile of mesenchymal stem cell use of various sources is considered 
safe, both experimentally and clinically.  
Cell and genetic therapies are considered innovative therapies for which 
there are no fully defined guides and guidelines in Brazil and on the world stage. 
However, in June 2015, the U.S. regulatory agency FDA (Food and Drug 
Administration) published a document entitled Considerations for the Design of Early-
Phase Clinical Trials of Cellular and Gene Therapy Products - Guidance for Industry 
representing the FDA's current recommendations on the first clinical studies with cell 
and gene therapy. The present study called ADORE-DH (EVALUATION OF THE DOSE-
RESPONSE OF CELLAVITA HD INVESTIGATIONAL PRODUCT AFTER INTRAVENOUS 
APPLICATION IN PARTICIPANTS WITH HUNTINGTON'S DISEASE) has as main objective to 
identify the dose of the Cellavita HD product that presents the best or most 
appropriate dose-response relationship, that is, that provides maximum efficacy and 
is considered safe. The definition of the most appropriate dose in the early stages of 

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the clinical study is decisive for a more optimized clinical development (FDA, 2015; 
FDA, 2010; Chow & Chang, 2008). 
The target population of the ADORE-DH study will consist of participants 
of both genders, with laboratory diagnosis of Huntington's disease, with mild to 
moderate symptoms and that justifies the risks inherent to a new product, but at the 
same time, is able to provide results that can be interpreted for dose-response 
evaluation of the same.  
The methodology to be used for the evaluation of the primary outcome 
(identification of the best dose) will be the score obtained in the evaluation in the 
motor part of the UHDRS scale (motor test), since motor degradation is considered 
one of the main aspects of Huntington's disease (ADF, 2010; Paulsen et al., 2014). 
As secondary objectives, other components of the UHDRS scale will be evaluated, 
as well as BMI and morphological aspects of the central nervous system by Magnetic 
Resonance. The safety of the investigational product will also be evaluated through 
the incidence and classification of adverse events presented by the participants 
during the study.  
The intravenous route of administration will be used because it is 
minimally invasive and currently used in clinical studies using mesenchymal stem cell 
therapy for the treatment of various diseases, including those affecting the central 
nervous system such as multiple sclerosis, cerebral palsy and spinal cord injury 
(Kerkis et al., 2015a; Boncoraglio et al., 2010; Lee et al., 2008; 2012; Koç et al., 
2002; Ra et al., 2011; Weiss et al., 2013; Horwitz et al., 1999; 2002; Karussis et al., 
2010; Hare et al., 2009; Yamout et al., 2010; Liang et al., 2010a, 2010b; Sun et al., 
2007; Carrion et al., 2010; Mohamadnejad et al., 2007; Kharaziha et al., 2009; 
Wilson et al., 2015). The chosen doses represent the clinical experience with other 
products for cell therapy (Hare et al., 2009; Koç et al., 2002; Lazarus et al., 2005; 
Prasad et al., 2011). 
In relation to the proposed dosage, the basis of previous studies 
developed by the research group of Dr. Irina Kerkis in São Paulo, carried out in dogs 
with neurological sequelae derived from the distemper virus (human model of 
multiple sclerosis), in a genetic model of canine muscular dystrophy (Duchene 
muscular dystrophy) (Kerkis et al., 2008) and bone marrow aplasia (aplastic anemia 
in humans), using a regimen of 3 intravenous mesenchymal stem cell applications, 
with an interval of 30 days between each administration. The studies demonstrated 

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the safety of multiple administrations and, considering the treatment of neurological 
sequelae in dogs, the result was efficient in motor response, and 70% of treated dogs 
regained the ability to perform movements (unpublished data provided by Sponsor). 
Furthermore, previous studies in humans with graft-versus-host disease (DECH) 
have shown that multiple applications of mesenchymal stem cells have shown 
satisfactory clinical response in patients who were not responsive to a single dose 
(Ball et al., 2015; Chen et al., 2015, Erbey 2015). These data suggest that stem cell 
therapy can be performed through multiple applications, according to the patient's 
response to treatment.  
Thus, with the identification of the dose of the Cellavita-HD product that 
presents the best response, measured from the parameters established in this 
protocol, the next planned studies can be initiated. The present study coded as 
ADORE-DH, corresponds to the second study of the development plan for the 
process of registration of the Cellavita-HD investigational product with the competent 
agencies. 

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3. OBJECTIVES 
 
3.1. 
Primary objective of effectiveness  
The primary objective of this clinical trial is to identify the dose of Cellavita-
HD product that has the best clinical response. 
 
3.1.1. Primary variable 
Verified through the Score of the Unified Huntington's Disease Rating 
Scale (UHDRS) scale of the baseline in relation to the end of treatment (domain 
comprising the assessments: motor, cognitive, behavioral, functional capacity and 
independence. 
 
3.2. 
Secondary objectives of effectiveness 
The secondary objectives of the study are: 
a) Clinical neurological evaluation throughout the study; 
b) Overall assessment of Huntington's disease severity (CIBIS scale); 
c) BMI assessment;  
d) Assess the incidence of suicide attempts during treatment; 
e) Neurological evaluation by imaging. 
 
3.2.1 
Secondary variables 
The variables are as follows: 
a) 
Score of the UHDRS scale throughout the study (at each visit); 
b) 
Score of the CIBIS scale throughout treatment; 
c) 
Weight of the participant throughout the study;  
d) 
Score obtained in the suicide domain of the HAM-D scale during treatment; 
e) 
It will be assessed through the profiles obtained during the treatment of the 
following measures: 
• Cortical thickness; 
• Volume of the various brain structures, especially the core of the base, 
with special attention to the caudate; 
• Identifiable metabolic changes in proton spectroscopy. 
 

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3.3. 
Safety objective 
The safety of medicines will be evaluated through the incidence and 
classification of adverse events occurring between treatments regarding type, 
frequency and intensity. 
 
 
3.4. 
Study hypothesis 
It is expected that it is possible to identify the dose that presents the best 
therapeutic response compared to the doses administered when compared to the 
placebo group.  
 
 

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4. STUDY OVERVIEW  
 
4.1. 
Study design 
This clinical trial will be prospective, phase II, single-centric, randomized, 
triple-blind, with two-test doses, placebo-controlled. 
 
4.2. 
Phase  
Phase II 
 
4.3. 
Possible treatment groups 
The study will include 35 participants. Initially, participants will be 
randomized in ratio 2: 2: 1 in groups G1: lower dose (1x106 cells/by weight range), 
G2: higher dose (2x 106 cells/by weight range) or G3: placebo, i.e. of the 35 
participants, 14 will be randomized to the lowest dose group, 14 for the highest dose 
group or 7 for the placebo group. Thus, the groups listed below represent the groups 
in which participants can be included in the course of the study.  
 
 
• G1: Lower dose: dose of 1x106 cells/by weight range per administration.  
• G2: Higher dose: dose of 2x106 cells/by weight range per administration. 
• G3: Placebo: constituted by the vehicle of the investigational product. 
 
4.4. 
Duration of the study 
A phase of inclusion and uniformization lasting a maximum of 90 days will 
be part of the study; after this period, the participant will be included in the study and 
will begin the treatment and follow-up phase that will last 330 days. 
The total period of participation in the study will be up to 420 days from the 
period of uniformization of the study; that is, about 14 months approximately.   
 
4.5. 
Visit schedules 
15 scheduled visits are planned, including: inclusion and uniformity visits 
(V-3 to V-1), management visits of the investigational product (cycle 1- Visits 0, 1 and 
2; cycle 2 - Visits 4, 5 and 6; cycle 3- Visits 8, 9 and 10) and follow-up visits (Visit 3, 7 
and 11).  

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Figure  3. Study design. 
 
The visits foreseen in the study are specified in a summarized form below: 
• Visit -3 inclusion (V-3): -30 to -1 days before V-2; 
• Visit -2 (V-2):  up to 30 + 7 days after V-3 
• Visit -1 (V-1):  up to 30 + 7 days after V-2 
• Visit 0 (V0): first administration of cycle 1; up to 30 days after V-1, and may 
occur even on the same day; 
• Visit 1 (V1): second administration of cycle 1 (30 days after Visit 0 – window 
of + 5 days); 
• Visit 2 (V2): third administration of cycle 1 (60 days after Visit 0 – window of 
+ 5 days); 
• Visit 3 (V3): follow-up visit (90 days after Visit 0 – window of + 5 days); 
• Visit 4 (V4): first administration of cycle 2 (120 days after Visit 0 – window of 
+ 5 days); 
• Visit 5 (V5): second administration of cycle 2 (150 days after Visit 0 – 
window of + 5 days); 
• Visit 6 (V6): third administration of cycle 2 (180 days after Visit 0 – window of 
+ 5 days); 
• Visit 7 (V7): follow-up visit (210 days after Visit 0 – window of + 5 days); 
Uniformization 
Treatment Period / Evaluation 
Lower dose: 
1x106 cells/weight 
range 
Lower dose: 
1x106 cells/weight 
range 
Lower dose: 
1x106 cells/weight 
range 
Higher dose: 
2x106 cells/weight 
range 
Higher dose: 
2x106 cells/weight 
range 
Higher dose: 
2x106 cells/weight 
range 
Inclusion 
Visits 

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• Visit 8 (V8): first administration of cycle 3 (240 days after Visit 0 – window of 
+ 5 days); 
• Visit 9 (V9): second administration of cycle 3 (270 days after Visit 0 – 
window of + 5 days); 
• Visit 10 (V10): third administration of cycle 3 (300 days after Visit 0 – window 
of + 5 days); 
• Visit 11 (V11): follow-up visit/final visit (330 days after Visit 0 – window of + 5 
days); 
After the 11th visit, participants will enter an extension protocol. 
 
4.6. 
Panoramic description of the study - Study plan  
Participants should be informed about the objectives, methodologies, 
risks, benefits and their rights in the study, as well as the confidentiality and secrecy 
with which the collected data will be treated. If they agree to participate in the study, 
they must provide their consent by signing the two copies of the Informed Consent 
Form (ICF). 
• Inclusion (V-3) and beginning of uniformization: after signing the 
Informed Consent, the participant will undergo a medical evaluation, which will 
include obtaining his medical history and performing a physical examination. At this 
time, the demographic data (birth date, gender and race) will be recorded, as well as 
the record of the use of prior/concomitant medication by the participant and adverse 
events not related to the medication. Huntington's disease will be confirmed through 
the existing diagnostic report (PCR), however, if the participant has not performed 
the test or if he/she does not have the accessible test report, a blood sample should 
be collected for this laboratory test. Subsequently, the following procedures will be 
performed: blood and urine collection for laboratory tests (including pregnancy testing 
for women) and serology, ECG and magnetic resonance imaging for CNS evaluation. 
In addition, UHDRS (Unified Huntington's Disease Rating Scale), HAM-D and CIBIS 
scales will be applied. All V-3 procedures must be performed within a maximum 
period of 37 days. If the participant is considered eligible, the participant will be 
invited for the next visits (V-2 to V-1). During the visit V-3 it will also be given an 
identification card (participation card in clinical trial), in which data such as address(s) 

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and contact telephone number(s) of the Principal Investigator and staff professionals 
for possible emergencies will be contained (Annex 7).  
• Uniformization: V-2 (up to 30+7 days after V-3) the results of the 
inclusion tests will be evaluated. If the participant is considered eligible, the 
participant will start a period of uniformization, which will consist of 3 scheduled visits, 
including the inclusion visit (Visit -3), Visit -2 and Visit -1, held monthly, to monitor the 
clinical evolution and application of the UHDRS Scale, HAM-D and CIBIS. In all these 
visits will be performed urinary pregnancy test in female participants.  
• Randomization and initiation of treatment: in V0 (may occur on the 
same day or up to 30 days after V-1): eligible participants will undergo a new medical 
evaluation, which will include updating medical history and collecting urine (including 
pregnancy testing for women), as well as performing physical examination and 
verification of inclusion/exclusion criteria. The applications of the UHDRS (Unified 
Huntington's Disease Rating Scale), HAM-D and CIBIS scales will also be carried 
out. If able to continue in the study, participants will be randomized to 2:2:1 in the 
lower Dose (1x106 cells/by weight range), Higher dose (2x106 cells/by weight range) 
or Placebo group and will perform the first administration of Cycle 1.  
In this visit, participants will be admitted to the Intensive Care Unit (ICU) of 
the Research Center for a period prior to the administration of the investigational 
product and will remain for 06 hours after administration (the length of hospitalization 
may be extended at the discretion of the Principal Investigator) for evaluation of vital 
signs and clinical examination. Cardiac monitoring will be performed during 
hospitalization and urine will be collected for β-hCG testing in women. In this visit, as 
in all other scheduled visits, there should be the registration of concomitant/previous 
medications and adverse events. 
• Treatment: V1 (30 days after V0 - window of + 5 days) and V2 (60 days 
after V0 - window of + 5 days): participants will return to the Research Center for 
further medical evaluation (including urinary pregnancy test for women) and 
verification of discontinuation criteria. In these visits, the second and third 
administration of cycle 1 of Cellavita-HD or placebo products will occur, respectively. 
Similarly, participants will be hospitalized before the administration of the 
investigational product and will remain for 06 hours after the end of it for clinical 
evaluation (the length of hospitalization may be extended at the discretion of the 

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Principal Investigator), and the same procedures performed in Visit 0 will be 
performed in V1 and V2.  
                    
 
 
Figure  4. Cycle 1 visits. 
 
• Follow-up: in V3 (90 days after V0 - window of + 5 days), participants 
will return to the Research Center for medical evaluation and verification of 
discontinuation criteria, in addition to collecting blood and urine laboratory tests 
(including urinary pregnancy test for women), as well as performing ECG.  UHDRS 
(Unified Huntington's Disease Rating Scale), HAM-D and CIBIS scales will also be 
applied. There will be the registration of concomitant/prior medications and adverse 
events. 
• Treatment: Visits V4 (120 days after V0 - window of + 5 days), V5 (150 
days after V0 – window of + 5 days) and V6 (180 days after V0 – window of + 5 days) 
represent, respectively, the first, second and third administration of cycle 2, and in 
each visit the participants will undergo an update of the medical history and 
verification of the discontinuation criteria and ECG performed during the evaluation 
visit. Participants considered fit will be admitted to the Intensive Care Unit (ICU) of 
the Research Center for a period prior to the administration of the investigational 
product and will remain for 06 hours after the end of administration (the length of 
hospitalization may be extended at the discretion of the Principal Investigator) for 
evaluation of vital signs and clinical examination. In these visits, there should be the 
registration of concomitant/previous medications and adverse events. Applications of 
the UHDRS (Unified Huntington's Disease Rating Scale), HAM-D and CIBIS scales 
will also occur. Furthermore, in Visit 4, the laboratory and urine tests (including 
urinary pregnancy test for women) of the previous visit will be evaluated. 
 

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Figure  5. Cycle 2 visits. 
 
 
• Follow-up: the Visit V7 (210 days after V0 with a window of + 5 days) 
represents a follow-up visit, and the same procedures and examinations performed in 
the V3 follow-up visit will be performed again in V7. 
• Treatment: the visits V8 (240 days after V0 - window of + 5 days), V9 
(270 days after V0 - window of + 5 days) and V10 (300 days after V0 - window of + 5 
days) represent, respectively, the first, second and third administration of the last 
cycle (cycle 3) of administration, which will occur similarly to previous cycles, the 
same procedures mentioned during the hospitalization period. 
 
 
Figure  6. Cycle 3 visits. 
 
Follow-up/Final Visit: V11 (330 days after V0 – window of ± 5 days): corresponds to 
the follow-up visit of the last cycle, as well as to the last visit of the study. On this 
visit, participants will return to the Research Center for medical evaluation and 
verification of discontinuation criteria, in addition to evaluating urine test results 

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(including pregnancy test for women).  Blood and urine will be collected for further 
laboratory tests, magnetic resonance imaging of the CNS, as well as ECG.  The 
UHDRS (Unified Huntington's Disease Rating Scale) HAM-D and CIBIS scales will 
be applied to participants. On the same day there will be the registration of 
concomitant/previous medications and adverse events. 
 
If any test result is altered, the participant will be contacted for an 
extraordinary visit to take the relevant procedures to the case. 
 

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5. STUDY POPULATION 
 
5.1. 
Population description 
Thirty-five participants of both genders, aged between 21 and 65 years, 
with laboratory (genetic) diagnosis of Huntington's disease and presenting the 
eligibility criteria determined for the study will be included. 
 
5.2. 
Inclusion and exclusion criteria  
The inclusion and exclusion criteria of the study are: 
 
5.2.1. Inclusion criteria 
a) Providing informed consent in writing, signed and dated; 
b) Participant of both genders aged ≥ 21 and ≤ 65 years*; 
c) Present confirmatory diagnostic report (PCR) of Huntington's disease with 
a number of CAG repeats on chromosome 4, greater than or equal to 40 
and less than or equal to 50 (if the participant has not taken the exam 
and/or if he does not have the exam report accessible, a new examination 
should be performed);  
d) Getting 5 points or more in the motor evaluation of the UHDRS scale 
(Unified Huntington's Disease Rating Scale) at the time of inclusion; 
e) Obtaining 8 to 11 points in the functional capacity of the UHDRS scale at 
the time of inclusion. 
*Note: The age of the participant will be considered on the day of the inclusion visit (V-3). 
 
5.2.2. Exclusion criterion 
a) Participant of the research who has participated in protocols of clinical 
studies in the last 12 (twelve) months, unless the researcher considers that 
there may be direct benefit to it (Resolution CNS 251, of August 7, 1997, item 
III, subitem J); 
b) Diagnosis of juvenile Huntington's disease*; 
c) Diagnosis of epilepsy; 
d) Diagnosis of major cognitive disorder; 
e) Decompensated active psychiatric disease; 
f) Current or past history of neoplasia; 

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g) Current history of severe and uncontrolled gastrointestinal, hepatic, renal, 
endocrine, 
pulmonary, 
hematological, 
immunological, 
metabolic, 
or 
cardiovascular disease; 
h) Diagnosis of any active infection, be it viral, bacterial, fungal or caused by 
another pathogen; 
i) Participant who has contraindication to the tests performed in this study, 
such as having a pacemaker or surgical clip; 
j) Alcohol and drug abuse (previous diagnosis according to the criteria of the 
Diagnostic and Statistical Manual of Mental Disorders - DSM V); 
k) Use of illicit drugs; 
l) Present positive results in one of the serological tests: HIV 1 and 2 (Anti-
HIV-1.2), HTLV I and II, HBV (HBsAg, Anti-HBc), HCV (anti-HCV-Ab) and 
FTA-ABS (Treponema pallidum); 
m) History of drug allergy, including contrasts for imaging, or bovine 
products; 
n) In use or foresight of the use of immunosuppressive drugs or prohibited 
drugs (item 6.9) during the first three months after the first administration of 
the investigational product; 
o) Any clinical change that is interpreted by the Investigator physician as a 
risk to the inclusion of the participant in the study. 
*Note: The diagnosis of juvenile Huntington's will be defined by the presence of 60 or more CAG repeats in the 
confirmatory diagnostic report for the disease and the appearance of characteristic signs and symptoms before 
the age of 21 (Nance, 2001). 
 
5.2.3. Discontinuation criteria (interruption) of treatment with the 
investigational product:   
Study participants are free to withdraw their consent and/or discontinue 
their participation in the study at any time, without prejudice to further treatment, as 
well as penalty or loss of benefits.   
In addition to withdrawing consent, study participants may be discontinued 
for any of the reasons described below: 
a) Study abandonment or loss of follow-upa ; 
b) Adverse events at the investigator's discretionb ; 

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c) Fulfilling any of the exclusion criteria of the study (newly developed or not 
previously identified criteria), which at the investigator's discretion 
prevents him from remaining in the study (risk x benefit assessment); 
d) Violation of the protocol, at the discretion of the Investigator and/or 
Sponsor; 
e) Discontinuation of the study by Sponsor; 
f) Death; 
g) Need for the use of prohibited concomitant medications that at the 
investigator's discretion may interfere with the results of the investigational 
product of the study (item 6.9); 
h) Any other clinical, laboratory or psychological condition, which in the 
opinion of the Investigator, is likely to discontinue treatment. 
a In cases where there is loss of follow-up of the research participant, defined as "no return of the participant on the scheduled 
date", the Research Center should make telephone contact within a maximum period of one (1) business day after the 
scheduled visit. The procedure must be registered in a source document, and the new scheduled visit, respecting the maximum 
period of two (2) days. In situations where the telephone contact is not effective, a telegram should be sent to the research 
participant requesting the contact urgently. After two (2) telegrams with an interval of 5 working days, the participant of the 
research should be classified as abandonment. Telephone contact attempts as well as confirmations of receipt of telegrams 
must be recorded/attached to the source document of the research participant. 
 
b Participants whose permanence in this study is interrupted by adverse events should be followed up until the resolution of the 
event. Their data will be included in the adverse event notification forms and considered for the efficacy and safety assessment 
of the investigational product used in this study. 
 
5.3. 
Selection failure 
The occurrence of participants who sign the informed consent and are not 
eligible before randomization will be considered a selection failure. All clinical records 
for participants representing selection failures will be collected in the source 
document. All participants considered selection failures will be replaced. 
The rescreening of participants who failed to meet the inclusion and/or 
exclusion criteria will be allowed, if the criteria are reversible and may re-fit the 
eligibility criteria.  
 
5.4. 
Replacement of study participants 
Only participants considered selection failures will be replaced. There will 
be no replacement for those who are discontinued after randomization. 
 
 
 

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5.5. 
Follow-up of research participants whose continuation in this study is 
interrupted 
Research participants excluded due to the emergence of adverse events 
(AEs) of any extension, related to the use of the product or not, will be monitored by 
the Research Center and monitored by Sponsor until its outcome. All necessary 
support will be provided for their clinical condition to be restored, i.e. stabilized at an 
acceptable level in the Investigator's assessment, and the costs are paid by Sponsor.  
Research participants excluded for other particular reasons or for non-
compliance with one of the study criteria will not be followed up once the non-
occurrence of AEs has been established.  
 
5.6. 
Recruitment strategies 
Participants will be recruited for a natural demand from people diagnosed 
with Huntington's disease after the study is released under the regulatory rule of 
disclosure of clinical studies.  
This recruitment strategy is considered specific for the target population 
and therefore presents a high eligibility rate for participants with diseases considered 
rare. 

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6. STUDY TREATMENT 
 
6.1. 
Identification of the investigational product  
The Cellavita-HD product contains viable human mesenchymal stem cells 
of allogeneic deciduous tooth pulp (of the same species but genetically different), in 
the form of a liquid suspension, as described in Table 01. The cells are not 
genetically modified.  
 
Table 01. Description of Cellavita-HD investigational product 
Product 
Cellavita-HD 
Characteristics and physical status 
Liquid suspension of allogeneic cells 
Concentration 
1x106 Cells 
Excipients 
0.9% sodium chloride containing 10% HSA 
Storage conditions 
Cryopreservation -196º C  
Pharmaceutical form 
Suspension for infusion  
Administration route 
Intravenous use 
Data provided by Sponsor 
 
6.2. 
Treatment groups  
The treatment groups will be arranged as follows:  
 
• 
G1: Lower dose: 1x10 dose6 cells/by weight range per administration.  
• 
G2: Higher dose: 2x10 dose6 cells/by weight range per administration. 
• 
G3: Placebo: constituted by the vehicle of the investigational product. 
 
6.3. 
Dosage 
In this study, two different doses of the investigational product will be 
evaluated (1x106 cells/by weight range and 2x106 cells/weight range) compared to 
placebo. Therefore, each participant will receive according to randomization, one of 
the fractional doses of Cellavita-HD product in 0.9% saline or placebo. 
Each participant will receive three cycles of three consecutive 
administrations (one every 30 days) with the drug according to randomization.  The 
interval between cycles will be 30 days. The following table also summarizes the 
distribution of participants among the treatment groups, as well as the dosage and 
the route to be used. 
 

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Table 02. Possible treatment groups in the ADORE-DH study 
Group 
Dose 
Dosage 
Administration 
Investigative 
Product 
Way 
G1 
Lower dose 
1x106 
cells/weight 
range 
3 administrations 
(one every 30 days) 
per cycle 
Cellavita-HD 
Intravenous 
G2 
Higher 
dose 
2x106 
cells/weight 
range 
3 administrations 
(one every 30 days) 
per cycle 
G3 
Placebo 
Investigational 
product 
vehicle 
3 administrations 
(one every 30 days) 
per cycle 
Placebo 
Intravenous 
 
6.4. 
Treatment allocation / Concealment of allocation  
The study will be randomized, including a ratio of 2:2:1 (14:14:7 
participants, in the lower dose, higher dose and placebo groups, respectively) and 
the allocation of treatment will be performed through a randomization list generated 
by the person responsible for the statistical analysis of the study.  
• G1 (lowest dose) = 14 participants; 
• G2 (highest dose) = 14 participants; 
• G3 (placebo) = 7 participants. 
The Research Center will receive the identification code of the packaging 
containing the investigational or placebo products to be dispensed according to the 
order of inclusion of the participants.  
 
6.5. 
Study blinding / Procedure for blind breakage 
The study will be triple-blind, blind to the participant, the Researcher and 
those responsible for evaluating the parameters of efficacy and safety. The 
responsible for the Pharmacy of the Research Center, a component of the non-blind 
team, will dispense the investigational product in the center for the use of 
participants. The study's medications will be supplied in identical-looking packages to 
maintain the masking of the study. Neither the Investigator nor his study team will 
know which medication the participant is using. In addition, those responsible for 
evaluating the outcome will receive the results in a coded (hidden) way.  
When necessary, for the safety and proper treatment of the participant, the 
Researcher may suspend the masking of the investigational product assigned to the 
participant, in order to define the appropriate treatment for clinical follow-up. The 
Investigator shall inform Sponsor of the breach of the blind code if it has not been 
notified previously.  

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Thus, if necessary, there will be the breaking of the blind code by opening 
the number of the medication kit from the randomization list. The reason for breaking 
the code must be recorded in the attendee's source document. 
The professionals responsible for the analysis of the safety and efficacy 
parameters defined in the study will also be blind elements, as well as the data 
manager and the statistician involved.   
For the accounting of the drugs used in the study, there will be a non-blind 
monitor designated for such function.  
The pharmacist or delegated professional will also be non-blind and will 
administer the drugs to the research participants. 
 
6.6. 
Packaging and labelling 
The statistician of the study will forward to the Sponsor and, only to the 
Sponsor, the sequential randomization list. Sponsor shall perform sample masking 
and proper product labeling, including the sequential number featured on the 
packaging, so that the investigational product is randomized by the Research Center 
which will include participants in the appropriate sequence. The head of pharmacy at 
the Research Center, a component of the non-blind team, will dispense the 
investigational product in the center for the use of the participants. Therefore, 
physicians and participants will not have access to the packaging of medicines. 
The product under investigation will be supplied on the packaging and will 
be labelled with the information necessary to identify the product intended for clinical 
research (Figure 7).  
 
 
Figure  7. Label template for products intended for research (A) Source: ANVISA; (B) Label model 
used for the study  
 
Sponsor: 
 
 
 
 
 
A 
Research Protocol: 
Responsible Investigator: 
Responsible Pharmacist: 
Dosage form: 
Batch: 
Manufacturing date (month/year): 
Expire date (month/year): 
Weight: 
Storage conditions: Keep at room temperature (15°C – 30°C). Protect from light and keep in 
a dry place. 
Use instructions: 
Route of administration: 
 
 ATTENTION! 
USE EXCLUSIVE IN CLINICAL TRIALS. 
ALL MEDICINES MUST BE KEPT AWAY FROM CHILDREN. 
This product must not be marketed. 
This product must not be used by another person. Its use is exclusive by the person for 
whom it was destined. 
This package must not be discarded and must be returned in the next visit together with the 
product, even if it was not used completely. 
This product must be used according to medical orientation. 
In case of doubt, please contact the Center and talk to: 
 
 
 
 
 
       B 
CELLAVITA-HD – Syringe 1 
hIDPSC in 0,9% saline solution 
 
Dose: n. of cells/kg of body weight  
Batch: 
 
Syringe volume: 
Total number of cells: 
Total number of viable cells: 
 
Viability: 
Storage conditions: 2 – 8°C 
Responsible for preparation: 
Date and time of preparation: 
 
Expiration: 
Waiting time for the application of the next syringe: 

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6.7. 
Storage and stability 
The investigational product will be stored in an appropriate location on the 
premises of Cellavita Pesquisa Científica Ltda (Sponsor), specifically in 
cryopreservation (liquid nitrogen -196ºC) and/or ultra-freezer (-80ºC) applications 
with temperature and access control, until the dates on which the administrations to 
the research participants will occur. Since Sponsor will have the product in custody 
most of the time, inventories as well as storage temperature control will be monitored 
by Sponsor, and any deviations from requirements, including the conducts employed, 
shall be recorded. After identifying any deviation, Sponsor shall judge whether it was 
significant and/or impactful on the quality and safety of the product, keeping it under 
quarantine or not, until cellular feasibility tests are performed to allow its use.  
On the scheduled date for the participant's hospitalization, the 
investigational product (ready for use according to the "Manual of presentation and 
instructions for administration of the Cellavita-HD product") will be forwarded to the 
Research Center in containers with thermal insulation transported according to the 
GCP, so that there is maintenance of its temperature. 
 
 
6.8. 
Chain of custody 
The investigational product will be provided by Sponsor in sufficient 
quantity (depending on the participant's weight and treatment group) on the 
scheduled date for administration. The receipt and conference of the product by the 
Pharmacy of the research center will be carried out by a delegated professional of 
the Research Center, which will include the verification of the lots, visual physical 
integrity and the transport temperature.  After the samples have been checked and 
the documentation regarding entry into the company have been completed, the 
products will be stored properly, according to the specifications of the "Manual of 
presentation and instructions for administration of the Cellavita-HD product" until the 
moment of infusion. 
All manipulation of the investigational product will be carried out in a 
standardized manner, in accordance with the specifications present in the "Manual of 
presentation and instructions for administration of the Cellavita-HD product" and in 
accordance with the Standard Operating Procedures (SOPs) of the research center. 
Handling, dispensing, disposal and/or loss (if applicable) will be recorded by the 

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responsible professional. The labels of the packaging used will be kept in the 
management record of the investigational product of each participant. 
The accounting of unused products will be carried out and they will be 
forwarded to Sponsor for disposal procedures. The chain of custody is summarized 
in Figure 8. 
 
Figure  8. Chain of custody flowchart 
 
6.9. 
Concomitant medicinal products prohibited during the study 
Any medicinal product administered during each administration cycle with 
cytotoxic/cytostatic or immunosuppressive action, such as: 
• Cytotoxic/cytostatic drugs: medicinal products belonging to the 
groups of nitrogen mustards, alkyl sulfonates, ethylenimines, methyl melamine, 
nitrosoureas and triazenes, as well as folic acid analogues, pyrimidine analogues and 
purine analogues. 
• Immunosuppressive drugs: azathioprine, tacrolimus, cyclosporine, 
prednisone, sodium mycophenolate, mycophenolate mofethyl, everolimus, sirolimus. 
In the specific case of immunosuppressive drugs, the withdrawal of the participant 
will be performed at the discretion of the Principal Investigator, considering the 
administered dose and the frequency of administration.   
Other drugs that may interfere with cell viability should be evaluated on a 
case-by-case basis. 
 
Sponsor 
Investigational Product 
Reception / Conference 
Monitored storage 
Dispensation 
Accounting of 
used and 
unused 
samples 
 
Return of the 
IP 

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7. SCHEDULE OF VISITS AND PROCEDURES OF THE STUDY 
 
7.1. 
Procedure for entry of Participants 
 
7.1.1. Informed Consent Form (ICF) 
The benefits and risks related to participation in the study will be explained 
to the participant before performing any procedures related to the study. If the 
participant agrees to participate in the study, the participant must sign, date and 
rubric in his own hand, two original copies of the ICF, as well as the Researcher 
and/or the person responsible for the application of the document. One of the signed 
copies will remain with the Investigator and the other must be delivered to the 
participant. 
If the research participant and/or his/her legal representative are unable to 
read and understand, an impartial witness must be present during the discussion of 
consent. After reading and explaining the Informed Consent, the research participant 
must orally provide his/her consent, and then his/her fingerprint must be collected in 
the document and the witness must sign and date the Informed Consent Form at the 
appropriate place. Due to the motor involvement characteristic of the studied 
condition, some participants may have difficulty writing their signature, despite being 
able from a cognitive point of view. For these participants, only the fingerprint should 
be collected in the document. 
The ICF must have been previously approved by the CEP responsible for 
the institution where the study will be conducted.  
 
7.1.2. Preserving the identity of research participants 
Participants will be selected according to the inclusion and exclusion 
criteria, consecutively (order of inclusion). After the research participant agrees to 
participate in the study and sign the Informed Consent, he/she will receive a code, 
which will identify him/her during the study. This code is composed of the initials of 
the first name, the middle name (if it does not exist, a dash "-") and the last name 
must be inserted (disregard names that refer to kinship, for example, Junior, Filho, 
Neto, etc.), followed by the date of birth in the format "DDMMYYYY".  So, we will 
have the following code as the example: 
 

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Figure  9. Participant code. 
 
The participant's code must be included in all documentation involving the 
participant and must accompany him/her from the beginning to the end of the study, 
in order to preserve his/her identity. 
In case of need for breach of confidentiality of the code, this will be done 
by the Principal Investigator, who will have access to the confidential coding data of 
the participants. Code breaking, which may occur in cases of health inspection, at 
Sponsor's request or at the discretion of the Investigator, must be carried out with the 
consent of the participant and the Investigator. The breaking of the codification 
without the participant's consent will only be performed in case of emergency. 
 
7.1.3. Acceptable contraceptive methods 
In this study, the following contraceptive methods are generally considered 
reliable 
when 
used 
correctly: 
oral 
contraceptives, 
contraceptive 
patches, 
contraceptive injection, male condom, diaphragm or cervical hood with spermicide, 
contraceptive vaginal ring, intrauterine device, surgical sterilization (bilateral tubal 
connection), vasectomized partner or sexual abstinence. 
The Researcher and the participant himself will decide the appropriate 
method of contraception that will be used during the study, which, when necessary, 
will be provided by Sponsor if he/she is not using any method of contraception.  
 
7.1.4. Exams performed for inclusion of study participants 
In the Visit V-3 (inclusion) the procedures described below will be 
performed, that corresponds to the selection exams and/or tests necessary to obtain 
Baseline measurements. Additional information about each procedure performed and 
its methodological specifications can be found in item 7.2. 
A. 
Laboratory diagnosis for Huntington's disease (PCR), if necessary; 
Initials of the 
participant 
Birth date: 
- 02 digits for the day 
- 02 digits for the month 
- 04 digits for the year 

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B. 
Clinical evaluation: anthropometric data, medical history and physical 
examination/vital signs (with BMI value); 
C. 
Laboratory tests: blood count, serum sodium, serum potassium, amylase, 
total cholesterol and fractions (LDL, HDL and VLDL), triglycerides, coagulogram 
(RNI, TAP and TTPA), alkaline phosphatase, glycated hemoglobin (HbA1c), urea, 
uric acid, TGO (oxalacetic glutamic transaminase), TGP (pyruvic glutamic 
transaminase), gamma-GT (gamma glutamyl transferase), total bilirubin and fractions 
(direct and indirect), serum creatinine, CK (creatine kinase) and CKmB (creatine 
kinase mB), β-hCG urinary for women and urine I; 
D. 
Serology: HIV 1 and 2 (Anti-HIV-1.2), HTLV I and II, HBV (HBsAg, Anti-
HBc), HCV (anti-HCV-Ab) and FTA-ABS (Treponema pallidum); 
E. 
Physician-reported electrocardiogram (ECG); 
F. 
Application of the UHDRS (Unified Huntington's Disease Rating Scale), 
CIBIS and HAM-D Scales; 
G. 
Evaluation of the CNS by magnetic resonance imaging of the brain. 
 
7.2. 
Study-specific evaluations and procedures 
 
7.2.1. Laboratory diagnosis for Huntington's disease (PCR) 
Where applicable, laboratory diagnosis of Huntington's disease will be 
carried out using the PCR methodology (polymerase chain reaction) during the visit 
(V-3), as published by Warner and collaborators (1993). The strategy of the genetic 
analysis used will be the determination of the number of repetitions of the CAG 
trinucleotide, contained in the 5' region of the IT15 gene, in 4p16 by PCR 
(sequencing). 
 
7.2.2. Clinical evaluation: demographic data, medical history and physical 
examination 
Participants will be clinically evaluated by the study physician, and the 
following items should be evaluated and recorded in the source document: 
a. Demographic data (birth date, gender and race); 
b. Medical history: 
 History of current pathology - Huntington's disease: 
 Start date; 

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 Evolution of signs/symptoms (includes motor, oculomotor, cognitive and 
psychiatric changes; 
 Background: 
 Personal history (other diagnoses/pathologies, dates and clinical 
evolution); 
 Family history; 
c. Physical examination and vital data: 
 Physical examination assessment: 
 General State:  the participant may be in good general condition (GGC), 
regular general condition (REG) or bad general condition (BGC); 
 The following should be evaluated: the degree of mucosal staining, 
hydration, perfusion (e.g., but not restricted to: clinical signs of cyaniasis) 
and respiratory pattern.  
 Overall assessment: includes cardiovascular, pulmonary, digestive, 
osteomuscular and peripheral systems, with emphasis on neurological and 
other evaluation, if necessary. 
 Evaluation of vital signs data: 
 Weight: preferably measured on a calibrated digital scale. At the time of 
measurement, the participant must be wearing light clothing (without 
wearing shoes and empty pockets). Body weight will be recorded in 
kilograms (Kg); 
 Height: a statometer (retractable train) attached to the digital scale will 
be used. During the procedure, the participant should be barefoot (or 
wearing socks) and position himself in the center of the equipment in an 
upright posture looking at a fixed point at eye height, with arms extended 
to the side of the body and palms facing back. The reading recorded after 
the measurement will be given in meters (m); 
 BMI: will be determined by the BMI equation = weight/height2 (kg/m2). 
According to the value found, the participant is categorized as thinness, 
eutrophy, overweight and degrees of obesity; 
 Blood pressure (BP): should be performed after the participant has 
remained at rest (without any physical effort) for at least 5 minutes. After 
this period, it will be checked 3 times at intervals of 1 to 2 minutes using a 
calibrated digital device. The measurement of the first measurement will 

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be discarded and the average of the last 2 measurements performed 
(ABP) will be recorded in a source document using the unit of 
measurement of millimeters of mercury (mmHg); 
 Heart rate (HR): includes checking the frequency (number of palpated 
or ascultated pulses), rhythm (regularity of heartbeat) and amplitude 
(quality of pulses felt). This parameter will be measured by palpation of the 
radial artery. The result will be reported using the bpm unit of 
measurement (beats per minute); 
 Body temperature: the measurement of the parameter will be performed 
using calibrated digital thermometer. The unit of measure used will be the 
centigrade scale, commonly called degrees Celsius (ºC). 
 
7.2.3. Laboratory tests and serology 
The tests to be performed in the study are described below. In visits in 
which there is the administration of the product, samples for laboratory tests should 
be collected before the beginning and after 06h 00min of the end of product 
administration. 
 
Table 03. Laboratory tests to be performed on V-3 and in all post-cycle follow-up visits (V3, V7, V11)                        
Category 
Test 
Normality values 
Hematological Analysis 
Hemogram 
(erytrogram, leukogram and 
platelet count) 
According to the reference 
values established by the 
laboratory. 
Biochemical Analysis 
 
Serum sodium 
Serum potassium 
Amylase 
Total cholesterol and fractions 
(LDL, HDL and VLDL) 
Triglycerides 
Coagulogram  
(RNI, TAP and TTPA)  
Alkaline phosphatase 
 Glycated hemoglobin (HbA1c) 
Urea 
Uric acid  
TGO 
TGP 
Gamma-GT 

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Category 
Test 
Normality values 
Total bilirubin and fractions 
 
Serum creatinine 
CK 
CKmB 
 
Urological Analysis 
Urine summary (urine I) 
Other 
β-hCG urinary (women-only) 
 
 
 
 
Table 04. Serological tests to be performed in the study at visits V-3 and V11. 
Serological Analysis 
HIV (1 + 2) (Anti-HIV-1.2) 
Negative 
HTLV I and II 
HBV (HbsAg and Anti-HBc) 
HCV (anti-HCV-Ab) 
FTA-ABS (syphilis) 
 
 
7.2.4. Cardiogram                                                         
For the monitoring of cardiac function, an electrocardiogram (ECG) of 12 
leads will be performed. The interpretation of the tracing should be performed by a 
physician and recorded both in the source document and in the individual clinical 
form (CRF) of each participant. Clinically significant abnormalities (and/or those 
related to current health condition) should be recorded as relevant medical history 
and/or current conditions during the Inclusion Visit (V-3), which should be judged by 
the Investigator Physician as a risk or not to inclusion in the study. Other clinically 
significant abnormalities found after product administration (compared to visit V-3) 
should be reported and evaluated by the Investigator physician as an adverse event.  
All ECG reports should be kept as part of the study documentation. 
The electrocardiogram will be performed during visit V-3, in the scheduled 
post-cycle visits (V3, V7 and V11), and on the days when there is administration of 
the investigational product, the evaluation will be carried out during the 6 hours of 
hospitalization after the end of the administration (before the dismissal of the 
participant). 
 
 

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7.2.5. Application of the UHDRS Scale (Unified Huntington's Disease Rating 
Scale) 
The UHDRS scale (Unified Huntington's Disease Rating Scale) is a clinical 
evaluation that presents 15 domains that assess motor, cognitive, behavioral and 
functional capacity functions. Each domain has from 0 to 4 categories, so that the 
higher the absolute value of the scale, the more severe the clinical situation of the 
participant.  The version translated to Portuguese of this scale is found in Annex 1, 
being considered valid and reliable for the Brazilian population according to the 
article by Tumas et al. (2004) (Barreto, 2009; Januário, 2011; Huntington Study 
Group, 1996).  
The motor evaluation (M) is obtained by the sum of the score of 31 items 
that evaluate different motor signs, which include oculomotor function (vertical and 
horizontal eye pursuit; saccadic movement – initiation and vertical and horizontal 
speed), orolingual movements (dysarthria and protrusion of the tongue), fine motor 
tasks (beats of fingers - right and left; pronation and supination - right and left), 
chorea (face, mouth, trunk and extremities), dystonia (trunk and extremities), 
parkinsonism and functions associated with gait. The score on this scale ranges from 
0 to 124 and the highest scores indicate greater motor impairment (Barreto, 2009; 
Januário, 2011; Huntington Study Group, 1996).  
This motor assessment may be filmed if the participant authorizes it by 
signing the Image Authorization Term. 
The cognitive assessment (P) is done by applying three tests that 
integrate the cognitive component of UHDRS:  
1. Verbal fluency test, which reflects the number of correct words
produced per minute (series of three) (Benton & Hamsher, 1978);
2. Test Stroop Color-Word (Stroop, 1935), which reflects the number
of correct items in the Stroop interference battery in a 45-second
period;
3. Digit-digit test (Smith, 1973), which reflects the number of items
produced in 90 seconds;
The Literal Verbal Fluency test is a test that assesses phonemic verbal 
fluency and the ability to establish verbal associations. The participant will be 
instructed to say the largest number of words started by a specific letter for 60 
seconds, as long as the words are not morphologically similar or proper names. This 

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test is repeated 3 times using 3 different letters, and the commonly used letters are 
'P', 'M' and 'R'. The total score is the sum of the number of words that the individual 
was able to say for the 3 letters (Barreto, 2009; Januário, 2011; Huntington Study 
Group, 1996).  
The Stroop test is composed by means of three elements: color naming, 
word reading and interference. The participant will be guided correctly before the 
start of the test, and the participant will start only after the test has been understood. 
The Researcher or professional delegated by him must ensure that the participant 
does not have color blindness and should align the nomenclature of colors in order to 
avoid double naming of them due to regionalism. The first element consists of a 
blade containing only circles and/or squares with specific colors, in which the 
participant should read as soon as possible and without the assistance of indication 
(fingers or instruments such as ruler or marker), the color he is seeing. The second 
element consists of a blade containing colored words that repeat themselves by 
changing the order and color of the words. The third element consists of a blade 
containing color names, where the color nomenclature is one, and the color in which 
it was printed is another (ex: red; the word "red" is written in black). For each 
evaluated element, the response time will be timed. The test score is performed 
according to the number of errors, as well as the time required to perform the test, 
according to the standardized table of normality (Appendix 2). 
The Digit-Symbol test (Digit span) is a test in which the participant must 
repeat the numerical sequence that the Investigator or professional delegated by him 
speak. This test consists of eight groups with two numerical sequences each, which 
must be reproduced in direct order and another with seven groups with two numerical 
sequences each, which must be reproduced in the reverse order in which it is spoken 
(E.g. 7 – 5    5 – 7). The test score is performed according to the number of correct 
answers; if the participant misses two consecutive numbers in the same sequence, 
the participant will lose points. The number of numbers stored by the participant 
(Span) will also be evaluated by the test. The score table with the normality values 
according to age as well as the Symbol-Digit test are shown in Annex 3.   
For all three cognitive tests, higher scores translate better cognitive ability 
(Barreto, 2009; Januário, 2011).  
The component of behavioral and psychiatric evaluation (B) of UHDRS 
aims to quantify the severity and frequency of neuropsychiatric symptoms 

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experienced by the participant. The evaluation score is obtained by the sum of 
different items (questions), each being defined by the product of gravity (0 = absent; 
4 = severe) and frequency (0 = absent; 4 = almost always) of psychiatric symptoms 
(sadness/mood, apathy, low self-esteem, anxiety, suicidal thoughts, aggressive 
behavior, 
intolerant 
behavior, 
obsessions, 
compulsions, 
delusions 
and 
hallucinations). The evaluation is done along the lines of semi-structured interviews, 
and the clinician has the flexibility to introduce additional questions that help identify 
psychiatric symptoms. The score ranges from 0 to 176, and the highest scores 
indicate greater behavioral impairment. The frequency of psychiatric symptoms is 
graded from 0 to 4, zero signifying the absence of symptom and four their existence 
and permanence. The severity of the symptom is also scored between zero, without 
any severity, and four, indicating greater severity of this symptom interfering in the 
activity of the individual. In accordance with the quantification proposal referred to by 
Marder et al. (2000), the frequency of a symptom is multiplied by the severity of it, in 
order to obtain a Score (Barreto, 2009; Januário, 2011; Huntington Study Group, 
1996). 
The functional evaluation (F) includes an independence checklist scale 
and an assessment of total functional capacity (TFC - Total Functional Capacity). The 
functional Checklist is included in a questionnaire of 25 questions that include various 
tasks of daily living, which are filled out through the information provided by the 
patient or his companion, in an affirmative or negative way. Each affirmative answer 
corresponds to one point, and the maximum score of 25 points represents greater 
functional capacity. A "Total Functional Capacity" (TFC), assesses the participant's 
ability to perform elementary, basic and instrumental daily life tasks such as 
maintaining profession and employment, taking care of oneself, managing finances, 
doing personal hygiene and food. This classification is made by the Investigator 
and/or person delegated by him, integrating both the information of the patient and 
his/her family members.  The TFC score may vary between scores 0 and 13, and the 
higher the score, the higher the functionality. Finally, the evaluation is complemented 
by an independence scale which classifies as a percentage the degree of 
dependence of the participant, and 100% corresponds to total independence, that is, 
greater functional capacity (Barreto, 2009; Januário, 2011; Huntington Study Group, 
1996).   
This scale will be performed at all study visits. 

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7.2.6. Application of the Hamilton Depression Assessment Scale (HAM-D) 
The Hamilton depression scale is multidimensional, hetero-evaluative of 
the observer, developed for application to patients previously diagnosed with mood 
disorder. At first, it was created to evaluate hospitalized patients and, therefore, has 
emphasis on melancholic and physical symptoms of depressive syndrome. 
Considered a "gold standard" by psychiatry, it allows the quantification of depressive 
symptoms, being useful for application in clinical practice and in clinical trials, 
particularly in the psychopharmacology of antidepressants.  
HAM-D originally has 17 items, which include the categories of mood, 
cognitive, somatic, motor, social and also anxiety. Thus, cognitive and somatic 
aspects represent 50% of the total score of the scale, while 16% refer to anxious 
symptoms and 8% to the mood category. The application of the scale should be 
performed by the Investigator or physician delegated by him, based on the 
presence/absence of the symptoms experienced by the participant in recent weeks, 
being ideal for application a time of up to 30 minutes. The score "zero" (0) should be 
given only when the symptom is absent, reduced due to symptomatic or dubious 
treatment. When there are doubts about the degree of intensity, one should always 
score to the most intense degree.  
For adequate scoring, it is essential that the applicator points immediately 
after the patient's response. To transform the points into scores, it is up to the 
evaluator to select one of the categories already published previously to obtain the 
cut-off point of the scale, which often compromises the comparison of the results in a 
more standardized way. In current practice, however, it is accepted that scores with 
more than 25 points characterize deeply depressed patients; scores between 18 and 
24 points, moderately depressed patients; and scores between 7 and 17 points, 
patients with mild depressive conditions. 
The intention of using the HAM-D scale in this trial is to evaluate, 
especially, the "suicide" domain, since one of the most frequent causes of death in 
patients with Huntington's disease is suicide.  
The full English HAM-D scale is available in Annex 4. This scale will be 
performed at all study visits. 

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7.2.7. CIBIS Scale Application – Clinician Interview Based Impression  
The CIBIS scale (Clinician Interview Based Impression of Severity) is an 
instrument of global assessment of the severity of the disease that associates the 
impression of the interviewer physician with the opinion provided by both the 
participant himself and the responsible caregiver. The application of the scale is 
simple and fast and has been widely used in clinical trials as a basis for evaluating 
the overall clinical change during treatment, especially in patients with 
neurodegenerative diseases (dementia, Alzheimer's, schizophrenia, among others).  
Initially, the baseline status of the patient is determined from a first interview (before 
the start of treatment), in which this information will serve as a reference to determine 
in later evaluations whether or not there were significant clinical changes throughout 
treatment. 
This evaluation is based on the observation of 15 domains related to the 
four categories that are part of the scale: cognition, behavior, social functioning and 
activities of daily living. It is not necessary for domains to be evaluated in a specific 
order. However, it is essential that each of them be examined and that observations 
are recorded in sufficient detail to facilitate subsequent evaluations. 
Each question is graded on a 7-point scale, 1 = Normal, not sick and 7 = 
Patient extremely ill. Therefore, the Interviewer should indicate based on the 
information provided by the participant/caregiver associated with their clinical 
experience, which score best classifies the severity of the disease. The version in 
English of this scale is found in Annex 5. This scale will be performed at all study 
visits. 
 
7.2.8. BMI Assessment (Body Mass Index) 
Body mass index (BMI) will be calculated from the relationship between 
body mass (in kg) and squared height (in m2) of the research participant. The BMI 
assessment will be carried out in all visits. 
 
 
 
 
 
BMI = weight (kg) 
 
 
 
 
 
 
height2 (m) 
 
 
 

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7.2.9. 
Evaluation of the CNS by magnetic resonance imaging of the brain 
The test will be performed on an MRI machine. Conventional sequences 
will be obtained, used for the screening obtained before and after the use of 
paramagnetic contrast (gadolinium). 
The sequences obtained will be submitted to a post-processing using the 
software FreeSurfer. This software is intended for the study of in vivo cortical and 
subcortical brain anatomy processed individually (evaluation of gray matter). The 
possibilities of FS are cortical surface reconstruction, cortical thickness calculation, 
cortical and subcortical structures segmentation, volumetric analysis, tractography 
analysis.  Spreadsheets will be used to group individual data and generate a 
database.  
 
 
Figure  10. Example of areas evaluated for average cortical thickness in the following regions of both 
hemispheres: prefrontal, lateral orbitofrontal, superior frontal and caudal anterior cingulate.  
 
The sequence by DTI (Diffusion Tensor Imaging) will also be evaluated for 
the purpose of studying the pathways of the brain white matter. The magnetic 
resonance tractography technique evaluates nerve fibers through the traces of the 
diffusion of water represented by a tensor, with the union of points and forming the 
image of a nerve pathway; this technique of RM tractography does not demonstrate 
fiber to fiber, but rather a set of them, indicating possible nerve paths by the white 
substance. The clinical applicability of the tractography is to measure the diameter of 
brain nerve fibers and their density, the state of myelinization in neurogenesis, 
evaluation of the degree of (de)myelinization throughout age and in cases of disease 
(Figure 11 and 12). 
 

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Figure  11. Figure of brain MRI using the DTI (tractography) sequence. 
Figure  12. Figure of MRI using DTI (tractography) sequence of the cerebellum, bulb, bridge, midbrain 
and brain. 
For the execution of this study, it may be necessary, depending on the 
clinical condition of the participant and the clinical evaluation performed by the 
physician, the use of sedative, in which it will be defined at the time of the 
examination which will be used. This evaluation will be carried out in visits V-3 and 
V11. 
7.3. 
Plan of visits and activities to be carried out at each visit 
7.3.1. Visit of inclusion and beginning of uniformization 

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A) Visit V-3: Inclusion (-37 to -1 days before V-2) 
• Signature of the ICF (Item 7.1.1);  
• Evaluation of inclusion and exclusion criteria (Item 5.2.1 and 5.2.2); 
• Recording of demographic data (date of birth, gender and race);  
• Medical evaluation: medical history and physical examination / vital signs data 
(Item 7.2.2 and 7.2.8) with BMI assessment - Body Mass Index; 
• Laboratory diagnosis for Huntington's disease, if applicable (Item 7.2.2); 
• Collection of blood and urine samples for testing:  
 Laboratory tests (Item 7.2.3 - Chart 3); 
 Serology (Item 7.2.3 - Chart 4); 
• ECG 12 leads performance (Item 7.2.4); 
• Application of the UHDRS, CIBIS and HAM-D scales (Item 7.2.5 to 7.2.7); 
• Performance of magnetic resonance imaging of the CNS (Item 7.2.9); 
• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Registration of prior/concomitant medication; 
• Record of adverse events not related to the drug; 
• Performance of β-hCG in women; 
• General guidelines. 
 
7.3.2. Uniformization period 
 
A) Visit V-2 (up to 30 + 7 days after visit V-3); 
• 
Evaluation of inclusion - except items "d" and "e" - and exclusion criteria (Item 
5.2.1 and 5.2.2); 
• 
Medical evaluation: updating of medical history and personal history, physical 
examination/ vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• 
Evaluation of the results of laboratory tests performed in the previous visit; 
• 
Evaluation of the results of serology tests performed in the previous visit; 
• 
Evaluation of ECG performed in the previous visit; 
• 
Evaluation of the CNS magnetic resonance imaging result performed during the 
previous visit; 
• 
Application of the UHDRS, CIBIS and HAM-D scales (Item 7.2.5 to 7.2.7); 

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• 
Record of adverse events/concomitant medication; 
• 
Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women;  
• Evaluation of laboratory examination for Huntington's disease, if applicable; 
• 
General guidelines.  
 
 
B) Visit V-1 (30 + 7 days after visit V-2); 
• 
Evaluation of inclusion - except items "d" and "e" - and exclusion criteria (Item 
5.2.1 and 5.2.2); 
• 
Medical evaluation: updating of medical history and personal history, physical 
examination/ vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• 
Application of the UHDRS, CIBIS and HAM-D scales (Item 7.5.5 to 7.5.7); 
• 
Record of adverse events/concomitant medication; 
• 
Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• 
Performance of β-hCG in women; 
• 
General guidelines.  
 
7.3.3. Treatment and Follow-up Visits 
 
A) Visit 0 (V0): 1st administration of cycle 1 (up to 30 days after V-1, which may 
occur on the same day) 
• Verification of inclusion - except items "d" and "e" - and exclusion criteria (Item 
5.2.1 and 5.2.2); 
• Medical evaluation: updating of medical history and personal history and physical 
examination/ vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• Randomization 
• Intravenous administration of the investigational product or placebo;  
• Hospitalization for a period prior to administration and for another 06 hours after 
the end of the same (the length of stay may be extended at the discretion of the 
Principal Investigator); 

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•
ECG monitoring during hospitalization time (during 06 hours after IP
administration) (Item 7.2.4);
•
Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7);
•
Record of adverse events (AEs) and concomitant medications;
•
Assessment of pregnancy risk and dispensation of contraceptive method, if
applicable;
•
Performance of β-hCG in women;
•
General guidelines.
B) Visit 1 (V1): 2nd administration of cycle 1 (30 ± 5 days after V0)
•
Verification of discontinuation criteria (Item 5.2.3);
•
Medical evaluation: updating of medical history and personal history and physical
examination / vital signs (Item 7.2.2 and 7.2.8) with BMI assessment;
•
Intravenous administration of the investigational product or placebo;
•
Hospitalization for a period prior to administration and for 06 more hours after the
end of the administration (the length of hospitalization may be extended at the
discretion of the Principal Investigator):
•
ECG monitoring during hospitalization time (during 06 hours after IP
administration) (Item 7.2.4);
•
Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7);
•
Record of adverse events (AEs) and concomitant medications;
•
Assessment of pregnancy risk and dispensation of contraceptive method, if
applicable;
•
Performance of β-hCG in women;
•
General guidelines
C)
Visit 2 (V2): 3rd administration of cycle 1 (60 + 5 days after V0)
•
Verification of discontinuation criteria (Item 5.2.3);
•
Medical evaluation: updating of medical history and personal history and general
physical examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment;
•
Intravenous administration of the investigational product or placebo;

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• Hospitalization for a period prior to administration and for 06 more hours after the 
end of the same (the length of hospitalization may be extended at the discretion 
of the Principal Investigator); 
• ECG monitoring during hospitalization time (during 06 hours after IP 
administration) (Item 7.2.4); 
• Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7); 
• Record of adverse events (AEs) and concomitant medications; 
• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women; 
• General guidelines 
 
D) Visit 3 (V3): follow-up visit (90 + 5 days after V0) 
• Verification of discontinuation criteria (Item 5.2.3); 
• Medical evaluation: updating of medical history and personal history and general 
physical examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• Collection of blood and urine samples for testing: 
 Laboratory tests (Item 7.2.3 - Chart 3) 
• ECG 12 leads performance (Item 7.2.4); 
• Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7); 
• Record of adverse events (AEs) and concomitant medications; 
• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women; 
• General guidelines. 
 
E) Visit 4 (V4): 1st administration of cycle 2 (120 + 5 days after V0) 
• Verification of discontinuation criteria (Item 5.2.3); 
• Medical evaluation: updating of medical history and personal history and general 
physical examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• Evaluation of the results of laboratory tests performed at the previous visit; 
• Evaluation of the ECG result performed in the previous visit; 

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• Intravenous administration of the investigational product at the given dose or 
placebo;  
• Hospitalization for a period prior to administration and for another 06 hours after 
the end of the administration (the length of hospitalization may be extended at the 
discretion of the Principal Investigator); 
• ECG monitoring during hospitalization time (during 06 hours after IP 
administration) (Item 7.2.4); 
• Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7); 
• Record of adverse events (AEs) and concomitant medications; 
• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women; 
• General guidelines. 
 
F) 
Visit 5 (V5): 2nd administration of cycle 2 (150 + 5 days after V0) 
• Verification of discontinuation criteria (item 5.2.3); 
• Medical evaluation: updating of medical history and personal history and general 
physical examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• Intravenous administration of the investigational product at the given dose or 
placebo;  
• Hospitalization for a period prior to administration and for another 06 hours after 
the end of the administration (the length of hospitalization may be extended at the 
discretion of the Principal Investigator); 
• ECG monitoring during hospitalization time (during 06 hours after IP 
administration) (Item 7.2.4); 
• Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7); 
• Record of adverse events (AEs) and concomitant medications; 
• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women; 
• General guidelines. 
 
 

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G)
Visit 6 (V6): 3rd administration of cycle 2 (180 + 5 days after V0)
•
Verification of discontinuation criteria (Item 5.2.3);
•
Medical evaluation: updating of medical history and personal history and physical
examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment;
•
Evaluation of the results of laboratory tests performed at the previous visit;
•
Intravenous administration of the investigational product at the given dose or
placebo;
•
Hospitalization for a period prior to administration and for another 06 hours after
the end of the administration (the length of hospitalization may be extended at the
discretion of the Principal Investigator);
•
ECG monitoring during hospitalization time (during 06 hours after IP
administration) (Item 7.2.4);
•
Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7);
•
Record of adverse events (AEs) and concomitant medications;
•
Assessment of pregnancy risk and dispensation of contraceptive method, if
applicable;
•
Performance of β-hCG in women;
• General guidelines.
H)
Visit 7 (V7): follow-up visit (210 + 5 days after V0)
•
Verification of discontinuation criteria (Item 5.2.3);
•
Medical evaluation: updating of medical history and personal history and physical
examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment;
•
Collection of blood and urine samples for testing:
Laboratory tests (Item 7.2.3 - Chart 3);
•
ECG 12 leads performance (Item 7.2.4);
•
Application of the UHDRS, HAM-D and CIBIS scales (7.2.5 to 7.2.7);
•
Record of adverse events (AEs) and concomitant medications;
•
Assessment of pregnancy risk and dispensation of contraceptive method, if
applicable;
•
Performance of β-hCG in women;
• General guidelines.

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I)
Visit 8 (V8): 1st administration of cycle 3 (240 + 5 days after V0)
•
Verification of discontinuation criteria (Item 5.2.3);
•
Medical evaluation: updating of medical history and personal history and physical
examination / vital signs (Item 7.2.2 and 7.2.8) with BMI assessment;
•
Evaluation of the results of laboratory tests performed at the previous visit;
•
Evaluation of the ECG result performed in the previous visit;
•
Intravenous administration of the investigational product at the given dose or
placebo;
•
Hospitalization for a period prior to administration and for another 06 hours after
the end of the administration (the length of hospitalization may be extended at the
discretion of the Principal Investigator);
•
ECG monitoring during hospitalization time (during 06 hours after IP
administration) (Item 7.2.4);
•
Application of the UHDRS, HAM-D and CIBIS scales (7.2.5 to 7.2.7);
•
Record of adverse events (AEs) and concomitant medications;
•
Assessment of pregnancy risk and dispensation of contraceptive method, if
applicable;
•
Performance of β-hCG in women;
• General guidelines.
J)
Visit 9 (V9): 2nd administration of cycle 3 (270 + 5 days after V0)
•
Verification of discontinuation criteria (Item 5.2.3);
•
Medical evaluation: updating of medical history and personal history and physical
examination/ vital data (Item 7.2.2 and 7.2.8) with BMI assessment;
•
Intravenous administration of the investigational product at the given dose or
placebo;
•
Hospitalization for a period prior to administration and for another 06 hours after
the end of the administration (the length of hospitalization may be extended at the
discretion of the Principal Investigator);
•
ECG monitoring during hospitalization time (during 06 hours after IP
administration) (Item 7.2.4);
•
Application of the UHDRS, HAM-D and CIBIS scales (7.2.5 and 7.2.7);
•
Record of adverse events (AEs) and concomitant medications;

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• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women; 
• General guidelines. 
 
K) Visit 10: 3rd administration of cycle 3 (300 + 5 days after V0) 
• Verification of discontinuation criteria (Item 5.2.3); 
• Medical evaluation: updating of medical history and personal history and physical 
examination/vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• Intravenous administration of the investigational product at the given dose or 
placebo;  
• Hospitalization for a period prior to administration and for another 06 hours after 
the end of the administration (the length of hospitalization may be extended at the 
discretion of the Principal Investigator); 
• ECG monitoring during hospitalization time (during 06 hours after IP 
administration) (Item 7.2.4); 
• Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7); 
• Record of adverse events (AEs) and concomitant medications; 
• Assessment of pregnancy risk and dispensation of contraceptive method, if 
applicable; 
• Performance of β-hCG in women; 
• General guidelines. 
 
L) Visit 11 (V11): final follow-up visit (330 + 5 days after V0)  
• Verification of discontinuation criteria (Item 5.2.3); 
• Medical evaluation: updating of medical history and personal history and physical 
examination/ vital signs (Item 7.2.2 and 7.2.8) with BMI assessment; 
• Evaluation of the ECG result performed in the previous visit; 
• Collection of blood and urine samples for testing:  
 Laboratory tests (Item 7.2.3 - Chart 3); 
 Serology (Item 7.2.3 - Chart 4); 
• MRI of the CNS (Item 7.2.9);  
• ECG 12 leads performance (Item 7.2.4); 

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•
Application of the UHDRS, HAM-D and CIBIS scales (Item 7.2.5 to 7.2.7);
• Record of adverse events (AEs) and concomitant medications;
•
Assessment of pregnancy risk;
•
Performance of β-hCG in women;
• General guidelines and exemption from the study.
Note.: If any participant presents a clinically significant result in any of the tests performed on V11, the 
participant will be contacted and an extraordinary visit will be made. 
7.4. 
Extraordinary Visits 
If the participant presents any adverse event or relevant signs and 
symptoms during the study period; or if the participant needs to be evaluated before 
regular visits, the participant should contact the Researcher or the Researcher 
himself can contact the participant if necessary. In such specific cases, the 
Investigator's assessment will be considered as an extraordinary visit.  
If the extraordinary consultation results in the withdrawal of the participant 
of the study, it will be considered as a closing visit and all activities related to the 
Final Follow-up Visit (V11) should be carried out.  
7.5. 
Adherence 
Since, for safety reasons, the experimental therapy used in the study will 
have the total dose divided into 3 administrations, one every 30 days, the participant 
who, for some eventuality, does not attend the scheduled administration dates will 
not be discontinued from the study, since that the disease in question is considered 
serious and has drug treatments only for the management of symptoms. Safety and 
efficacy data obtained from these participants will only be considered in the ITT 
population analysis. 
To increase the participant's adherence to the protocol, it will be discussed 
with the same in what the trial consists before his/her consenting, appointments will 
be scheduled at convenient times, expenses such as transportation and food will be 
reimbursed, and the participant will be encouraged to remain in the study. 

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8.
STATISTICAL PROCEDURES
   The study data will be recorded in the medical records of the research 
participant and will later be transcribed to the company's electronic CRF. The data 
inherent to the study will be tabled and sent to the statistician responsible for the 
study. Statistical analyses will be performed after the resolution of all inconsistencies 
and performance of data quality control.  
The disposition of screened participants, included in the study, who 
received medication, who prematurely discontinued or completed the study will be 
summarized by treatment dose. 
Demographic characteristics, pre-existing clinical conditions, medical 
history, previous treatments, reported at baseline will be summarized by treatment 
group, considering participants who received at least one dose of the drug under test. 
Graphs, tables and descriptive analyses will be carried out using an 
appropriate statistical system. 
8.1. 
Sample size determination 
The estimated number of participants was calculated considering 
clinical/regulatory and non-statistical assumptions. In this way, the document 
Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene 
Therapy Products - Guidance for Industry (FDA, 2015) predicts that a smaller sample 
size is considered appropriate for diseases considered fatal, where a major potential 
benefit may warrant an unknown risk. Additionally, considering conditions provided 
by the FDA document such as the still limited capacity of the investigational product 
manufacturing and the relatively rare prevalence of the target disease, Sponsor 
suggests the sample size of 35 participants, which is considered a feasible sample 
size and at the same time adequate to meet the proposed objective.  
8.2. 
Analysis Populations 
The analysis of the study data will be based on the following populations 
as described below: 

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8.2.1. Population Analysis of Intention to Treat (ITT) 
All participants who make use of the first administration of the 
investigational product of the study will constitute the population of intent to treat (ITT 
– intention-to-treat).
8.2.2. Population Analysis of Intention to Treat Efficacy (ITTe) 
All ITT participants who have made at least one efficacy assessment. 
8.2.3. Population Analysis Per Protocol (PP) 
All participants who, according to the protocol guidelines, do not present 
major deviations, will constitute the population per protocol (PP - per protocol).  
Major protocol violations will be reviewed before data analysis begins. 
8.2.4. Safety Analysis Population 
All participants who receive at least one administration of the 
investigational product of the study shall be included in the safety analysis 
population; identical to the ITT population. 
8.3. 
Measurement of the primary variable 
For the evaluation of the best dose-response, the score in the evaluation 
of the UHDRS scale (Unified Huntington's Disease Rating Scale)  was defined as the 
primary outcome. 
The evaluation of the primary variable will be performed considering the 
total result of the UHDRS scale. There will also be the evaluation of the composite 
UHDRS scale (cUHDRS). 
The reports will include analyses of the values at the time of inclusion (V-
3) in relation to the end of treatment (V11), as well as the analysis of the values of
the uniformization period (mean values of visits V-3, V-2 and V-1) in relation to the
end of treatment (V11).
The CAP score refers to the term in English CAG - Age Product (CAP), 
which is an index calculated in relation to age and length of CAG repetition. This 
score will be used in order to complement the measurement of the primary variable, 
so that the participant's age and CAG repetition are taken into account in the analysis 
of the results over time.  

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The CAP score formula is: CAP= {100 x Age (CAG -L)}/ S 
CAG being the number of repetitions on chromosome 4 (consider the 
allele with the highest numbering), L and S are constant (L=30 and S=627). In which 
"L" is a scale constant that anchors the length of the CAG approximately at the lower 
end of the distribution relevant to the pathology of HD. And "S" is a normalization 
constant chosen so that the CAP score is approximately 100 at the expected onset 
age of the patient, as estimated by Langbehn et al. 2004. For the calculation in this 
study, the Value of S used will be S = 627, which are estimates obtained by a 
reanalysis of the data of Langbehn et al presented by Warner and Hayden 2012. 
8.4. 
Measurement of secondary variables 
Secondly, the safety as well as preliminary evidence of efficacy of the 
Cellavita-HD investigational product will be evaluated through of the following 
variables 
a) Check for clinical neurological improvement throughout the study:
    The UHDRS scale will be evaluated at each visit to measure neurological 
improvement. 
b) Check the overall improvement in disease severity by the CIBIS scale
throughout treatment: 
The profile of the CIBIS scale will be considered for the evaluation of the 
overall clinical improvement of the participant through the treatments of the study. 
c) BMI assessment:
BMI (Body Mass Index) will be evaluated through BMI profiles obtained 
during treatment. 
d) Evaluate the suicide domain of the HAM-D scale throughout treatment:
It will be evaluated especially the domain "Suicide" by means of 
classification scores, in which scores of 8 – 13 correspond to mild depression, 14 – 
18 to moderate, from 19 - 22 to severe and above 23 points to very severe 
depression. The "suicide" domain of the HAM-D scale will be evaluated through the 
profiles obtained throughout the treatment. 

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e) Neurological evaluation by magnetic resonance imaging of the brain:
It will be assessed through the profiles obtained during the treatment of 
the following measures: 
- Cortical thickness measurements;
- Volumes of the various brain structures, especially the core of the base,
with special attention to the caudate; 
- Identifiable metabolic changes in proton spectroscopy.
8.5. 
Measurement of the Safety Variable 
During the study, the safety of the investigational product will be 
thoroughly assessed based on periodic evaluations including clinical, laboratory and 
imaging tests, so that any alteration is properly recorded. The safety data described 
below will be collected and recorded in the clinical file: 
•
Adverse events: all adverse events will be monitored and reported
in the clinical form of the study from the signature of the Informed
Consent, including type, frequency, intensity, seriousness, severity,
action taken and relationship with the investigational product of the
study. The adverse events may be reported by the research
participant or observed by the Researcher. Adverse events will be
standardized by the Investigator.
•
Changes in vital signs, clinical examination and medical
evaluations;
•
Changes in laboratory or serology tests:
•
Change in electrocardiogram (ECG);
•
Incidences and classification of benign and malignant neoplasms.
The results obtained will be presented through the proportion of adverse 
events that occur, segmented by dose of the investigational product. Any clinically 
significant abnormalities that persist until the end of the study will be monitored by 
the Principal Investigator until resolution or until a clinically stable outcome. 

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8.6.  Study hypotheses 
 
8.6.1. Primary Hypothesis  
Identify the dose of the Cellavita-HD investigational product that presents 
the best response.  
 
8.6.2. Secondary hypotheses  
Cellavita-HD is safe after intravenous administration in participants with 
Huntington's disease and provides evidence of efficacy in relation to the parameters 
evaluated.  
 
8.7. Statistical analysis 
The analyses will be carried out using an appropriate statistical system. 
 
 
8.7.1.1. 
Analysis of demographic and baseline data 
A description of the distribution of participants (number and percentage of 
randomized participants in the ITT and PP populations) will be provided by treatment. 
The analyses of the qualitative variables of the ITT population will be 
described by frequency analysis. The quantitative variables will be described by 
mean, standard deviation (SD), minimum, maximum and median. 
 
8.7.1.1.1. 
Hypothesis analysis 1 
The treatments will be compared using a linear model in which the 
response is the motor evaluation of the UHDRS scale at the end of the three 
treatment cycles; where the treatment will be the factor and the basal measurement 
will be the variable. 
Corrections will be made to multiple comparations (ANOVA).  
 
8.7.1.1.2. 
Analysis of secondary hypotheses 
The continuous (numerical) variables will be performed using a model of 
repeated measurements, including the factors treatment, time, interaction between 
time-treatment using the GEE method. 

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Analysis of residues will be carried out to evaluate the suitability of the 
model used. The multiple-way comparation method will take into account the 
adjustment of the significance level. 
      The analyses of categorical responses observed over time will take into 
account the factors treatment, time, time-treatment interaction. The significance level 
will be preserved with the preserved multiple-like comparation method. 
8.7.1.1.3. 
Analysis of the safety hypothesis 
The safety assessment will be performed at the end of each cycle and will 
be verified through the incidence of reports that adverse events occurred during the 
study, in relation to causality with the treatment under study. 
8.7.1.1.4. 
Exploratory analyses 
Additional exploratory analyses will be carried out if necessary to better 
understand the results. All methods used will be detailed described in the final study 
report. 
8.8. 
Data management plan summary 
The data of the study will be reviewed by the Data Management team and, 
if they present discrepancies, questions will be generated, which will be sent to those 
responsible for collecting them. A report will be issued with the questions raised and 
their answers / resolutions, which will be stored together with the other study 
documents. 
The data management of the clinical studies conducted complies with 
current regulations and in compliance with the processes described below. 
8.8.1. Deviations from the Original Statistical Plan 
Any deviation from the original statistical plan shall be described and 
justified in the protocol and/or final statistical report, where appropriate. 
8.8.2. Record of analyzed parameters 
All study data will be recorded in the research participant's medical 
records and will later be transcribed into the company's CRF. The data inherent to 
the study will be tabled and sent to the statistician responsible for the study.  

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8.8.3. Data Capture - Clinical Record (CRF)  
The clinical form of the clinical study will be used to record the data 
collected in the source documents, being considered an integral part of the clinical 
study. The process of evaluation, development and maintenance of the system is in 
accordance with the guidelines established by Article 21 part 11 of the CFR (Code of 
Federal Regulations) of the FDA. The tool will be validated prior to the beginning of 
data collection in accordance with the requirements established by Sponsor, in order 
to ensure its quality and performance.  
The clinical data will be imputed by the Investigator or by the delegate(s) 
responsible.  
The clinical form should be updated in order to express each phase during 
the clinical study, with the registration of all research participants who are screened, 
in order also to ensure the traceability of the records of the research participants 
considered as selection failures.  
 
8.8.4. Data validation – Plan of Queries  
The plan of queries describes the verification of data to be performed by 
data management, based on the crossing between different fields of the clinical 
record. Its development considers each field of the clinical record and the crossing of 
fields, within the same visit and between visits, allowing the verification of all fields 
considered primordial for statistical analysis and obtaining the results of the clinical 
study.  
Manual checks contained in the queries will always be performed by Data 
Management, in order to ensure the quality of the data collected.  
 
8.8.5. Database cleanup and freezing  
Based on the queries, the database's data cleansing is carried out in order 
to ensure the quality of the collected data. The cleaning of the bank is carried out 
periodically by generating batch of queries submitted to the Research Center with 
requests for clarification. At the end of data collection, the last batch of queries is 
forwarded and after the final cleaning of the data, freezing is performed. The freeze 
will be carried out according to the procedures of the company responsible for 
monitoring the database. 

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8.9. 
 Handling Missing or Invalid Data 
Safety will be analyzed using the observed data set and no techniques will 
be used for imputation of missing or invalid data. 
The analyses of the preliminary efficacy assessment will be performed 
using the LOCF principle, the last observation carried forward, for the absent post-
baseline data. In the analysis of repeated measures, the imputation of data will be 
performed using the GEE method. 
 
8.10. Interim analyses  
There will be no interim analysis of the data. 

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9. ADVERSE EVENTS 
 
9.1. 
Adverse events 
An adverse event is defined as any unfavorable medical occurrence, which 
may occur during treatment with an investigational drug/product, but which does not 
necessarily have a causal relationship with this treatment.  
All adverse events observed or reported spontaneously, regardless of the 
possible causal relationship with the investigational drug/product of the study, should 
be recorded on the Adverse Events page(s) of the clinical study form. Serious 
adverse events of any nature or unexpected events should be notified to Sponsor via 
specific Pharmacovigilance form.  
Alterations (abnormalities) in the physical examination, considered as 
clinically significant by the Investigator, prior to the use of the investigational product 
should be reported in physical and/or historical clinical evaluation (if applicable) and 
if, after use of the drug, relative worsening, worsening of conditions or appearance of 
changes (abnormalities) during regular visits, these should be recorded as adverse 
events. 
Changes (abnormalities) in the laboratory testing, considered as clinically 
significant by the Investigator and present in the period in which the participant does 
not use the medicine/ investigational product should also be recorded as adverse 
events. All laboratory alterations (abnormalities) should always be recorded in the 
participant's medical records. 
For all adverse events, the Investigator should seek appropriate 
information, both to determine the consequence of the adverse event and to assess 
whether it is within the classification criteria as a serious adverse event, meaning that 
it requires immediate notification. The follow-up of the adverse event, even after the 
date of interruption of the study, will be necessary in case of persistence of the event 
or its sequelae. Such follow-up is necessary until the adverse event or its sequelae 
disappear or stabilizes to an acceptable level in the Investigator's assessment. 
 
9.1.1. 
Serious adverse events 
Serious adverse events include any undesirable medical occurrence that, 
at any dose: 
• Results in death; 

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• Threatens life; 
• Results in permanent or significant disability; 
• Requires hospitalization or prolongation of hospitalization; 
• Results in congenital anomaly; 
• Constitutes other clinically important events (an event that may result in one 
of the consequences described above if not properly treated). 
A person's substantial loss of competence in performing his or her routine 
duties is defined as incapacity. 
It should be emphasized that, regardless of the above criteria, any other 
events that, in the Investigator's opinion, are considered serious, should be 
immediately reported. 
All serious adverse events, regardless of the possible causal relationship 
with the study drug, should be immediately (within 24 hours) reported in the form of a 
severe adverse event reporting form filled out with all event data in the most detailed 
way possible and forwarded back to Sponsor.  
The research ethics committee (CEP) should also be informed of serious 
adverse events. 
Any serious adverse events occurring during the study shall be reported 
within 24 hours to Sponsor from the knowledge of the fact by the Center, regardless 
of the circumstances or probable cause, whatever the subsequent consequences. 
 
9.1.2. Classification of adverse events according to expectation 
 
• Unexpected adverse event: it is defined as any harmful experience that is 
not described in the research product leaflet, including events that may be 
symptomatic and physiologically related to an event described in the leaflet, but 
which differ from this event by the degree of severity and specificity. In addition, the 
adverse event whose nature, severity or outcome is inconsistent with the information 
contained in the leaflet is considered unexpected. 
• Expected adverse event: it is defined as any adverse event whose nature 
or intensity is part of the information contained in the leaflet (for marketed medicines / 
investigational products) or in the Investigator's Brochure (for medicines / 
investigational products) in clinical research phase. 

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9.1.3. Classification of adverse events in terms of intensity 
The classification of the intensity of adverse events will be performed 
according to the degree of qualifying intensity for health conditions (WHO) described 
below:  
• Mild: a problem is present less than 25% of the time, with an intensity that a 
person can tolerate and that rarely happens in the last 30 days.  
• Moderate: it is a problem that is present less than 50% of the time, with an 
intensity, which is interfering in the day-to-day of people and that happens 
occasionally in the last 30 days.  
• Severe: it is that a problem that is present in more than 50% of the time, with 
an intensity that partially alters the day-to-day of people and that happens frequently 
in the last 30 days.  
• Complete commitment: it is a problem that is present in more than 95% of 
the time, with an intensity that completely alters the day-to-day of the person and that 
occur every day for the last 30 days.  
• Unspecified: It means there's not enough information to specify the 
intensity.  
• Not applicable: it is inappropriate to use a gradation (e.g. menstrual 
functions).  
 
 
9.1.4. Causality categories: WHO-UMC System 
 
a) Certain / Defined 
• Event or alteration (abnormality) in laboratory examination with plausible 
temporal relationship in relation to the administration of the intervention. It cannot be 
explained by disease or other intervention or medicine; 
• Response to discontinuation or plausible withdrawal (pharmacologically, 
pathologically); 
• Event defined pharmacologically or phenomenologically (e.g., an objective 
and specific disorder or a pharmacologically recognized phenomenon); 
• Satisfactory re-exposure if necessary. 
 

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b) Probable 
• Event or alteration (abnormality) in laboratory examination with a reasonable 
temporal relationship in relation to the administration of the intervention; 
• Unlikely to be attributed to a disease or other intervention, medicinal product; 
• Response to clinically reasonable discontinuation or withdrawal; 
• Re-exposure not required. 
 
c) Possible 
• Event or alteration (abnormality) in laboratory examination with a reasonable 
temporal relationship in relation to the administration of the intervention; 
• It can be explained by disease or other interventions, medicines; 
• Information about withdrawal or discontinuation of treatment may be missing 
or obscure. 
 
d) Improbable 
• Event or alteration (abnormality) in laboratory examination that, in relation to 
the time of administration of the intervention, makes an unlikely (but not impossible) 
relationship; 
• Disease or other treatments provide plausible explanations. 
 
e) Conditional / Unclassified 
• Event or alteration (abnormality) on laboratory examination; 
• More data is needed for an appropriate assessment, or; 
• Additional data under investigation. 
Source: The Uppsala Monitoring Centre – World Health Organization 
 
9.2. 
Contact with the Sponsor 
The names and contact phones of the Principal Investigator, among 
others, are listed at the beginning of this protocol and will be made available to 
research participants together with the ICF for any consultations. 
 
 
 

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9.3. 
Follow-up of reports of adverse events 
For all reports of adverse events regardless of their severity, in case there 
is any inconsistency in the registration and/or evaluation of the adverse event(s), it is 
the responsibility of the Investigator to obtain and provide the information to Sponsor. 
In the final follow-up of the monitoring, the monitor should check the 
Clinical Form(s) if there are adverse events with a "not recovered" clinical outcome. 
For these reports, the monitor should ask the Investigator to follow-up and collect 
outcome information. 
 
After the end of the study, the Investigator shall be responsible for 
informing Sponsor of any adverse event occurring within thirty (30) days, reported to 
them spontaneously, after the clinical study is completed or discontinued, if there is a 
possibility of a causal relationship between the adverse event and the product under 
investigation. 
 
9.4. 
Reports of pregnancy occurrence with direct or indirect exposure to the 
investigational product of the study 
In cases of pregnancy during clinical studies, we aim to assess toxicity in 
women and fetus directly through the passage of the product under investigation 
through the placental barrier (pregnancy with direct exposure to the medication under 
study) or due to the transfer of the product under investigation to the woman through 
the semen of the research participant (pregnancy with indirect exposure to the 
medication under study), therefore, both direct and indirect pregnancy should be 
analyzed with appropriate follow-up. 
 
9.4.1. Gestational follow-up 
The Investigator should follow-up on the evolution of pregnancy (with 
direct or indirect exposure to the medication under study) until the end of pregnancy 
and birth of the child, even after the exclusion of the research participant from the 
clinical study, considering that such information is important for the evaluation of the 
safety profile of the product under investigation. 
 
 
 

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9.4.2. Pregnancy with direct or indirect exposure to the investigational 
product under study 
For research participants who may become pregnant after signing the 
Informed Consent, regardless of exposure to the product under investigation, 
gestational follow-up will be required, as described below: 
• At the time of pregnancy knowledge; 
• End of the 1st trimester: preferably between the 12th and 16th weeks, 
with ultrasound presentation; 
• End of the 2nd trimester: preferably between the 24th and 28th weeks, 
with ultrasound presentation; 
• End of the 3rd trimester: preferably between 36th and 40th weeks, with 
ultrasound presentation; 
• After the birth of the child until the first year of life. 
 
9.4.3. Notification to the Research Ethics Committee (CEP) 
Although pregnancy is not a serious adverse event from a medical point of 
view, regulatory treatment is the same as a serious adverse event; therefore, the 
Research Ethics Committee (CEP) should be informed of cases of pregnancy 
occurring within a maximum of 24 hours, after knowledge by the Research Center, 
through its responsible investigators. 
 
9.4.4. Consistency of information notified by Research Center to the Sponsor 
In case of possible inconsistencies in the registration of the serious 
adverse event and/or pregnancy in the forms, the monitor will request clarification 
from the investigator. This communication will take place through monitoring reports 
and/or clarification letters. 
 
9.5. 
Expected adverse events with cell therapy  
Few adverse events have been reported after administration of 
mesenchymal stem cells in terms of immediate toxicity, infusion and late effects. 
Thus, as the number of patients on therapy with this type of cell is still relatively 
small, adverse events and safety related to it have not yet been fully elucidated. 
However, in some specific pathological cases, the use of mesenchymal stem cells 

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was related to the appearance of neoplasms (history of neoplasms) and worsening of 
arthritis (history of arthritis) (Wang, Qu & Zhao, 2012). 
In order to gather information on adverse events related to mesenchymal 
stem cell therapies and to support their use in clinical studies, Lalu et al. (2012) 
conducted a meta-analysis in which no significant associations were verified between 
treatment with mesenchymal stem cells (of several lines) and the development of 
acute infusion toxicity, systemic complications, infections, neoplasms or deaths. 
However, the authors found that although there is a significant correlation between 
cell therapy and the onset of transient fever, it is possible to observe good tolerability 
and safety (Lalu et al., 2012). 
Although the appearance of neoplasms is a risk to the use of cell 
therapies, the analysis performed by the authors did not find an association between 
both. The emergence of this correlation started from non-clinical studies that 
demonstrated neoplastic increase in animals treated with therapy, however, in 
current clinical studies the occurrence of neoplasia presented was low and present 
only in patients with a history of neoplasms (Lalu et al., 2012). 
Thus, the authors concluded that despite the need for broader and more 
controlled clinical studies involving the use of mesenchymal stem cells for long 
periods, so far there is no evidence that this therapy represents a safety risk to 
humans (Lalu et al., 2012).  
This way, due to the variety of theoretical risk factors involving this 
therapy, a thorough clinical evaluation should be performed, taking into account the 
risks and benefits that treatment may present for the patient. This assessment at the 
beginning and during follow-up of cell therapy can help determine the extent and 
focus of safety plans for such treatment (Herberts, Kwa & Hermsen, 2011; Wang, Qu 
& Zhao, 2012). 
The table below summarizes the possible theoretical risk factors involving 
the use of cell therapy with mesenchymal stem cells of several lines. 
 
 
 
 
 
 

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Table 05. Theoretical risk factors involved in mesenchymal stem cell therapy. 
Factors 
Possible risks 
Intrinsic 
•
Rejection of administered cells
•
Susceptibility to opportunistic diseases
•
Grafting cells in an unwanted location
•
Unwanted biological effect (differentiation in vivo in
unwanted cell types)
•
Toxicity (infusion or systemic) (Symptoms: transient fever,
bronchospasm and/or laryngospasm, chills, diarrhea,
dyspnea, headache, facial edema, glottis and/or larynx,
fever, hemoglobinuria, hypotension, nausea, itching, facial
flushing, 
abnormal 
bleeding, 
sweating, 
tachycardia,
dizziness, hives, and vomiting).
•
DMSO toxicity (Symptoms: cough, flushing, rash, chest
tightening 
and 
wheezing, 
nausea 
and 
vomiting,
cardiovascular instability).
•
Formation of neoplasms (malignant or benign)
Extrinsic 
•
Transmission of diseases
•
Reactivation of latent viruses
•
Unwanted immune response
•
Cell contamination (with unwanted cells, culture media
components or chemical compounds); 
•
Mixture of autologous patient material
•
Cardiac, 
vascular, 
renal, 
neurological, 
pulmonary,
hematological or hepatic dysfunctions
•
Formation of neoplasms (malignant or benign)
Source: Circulation of Information for use of cellular therapy products – Revised November 2013. 
Helberts, Kwa & Hermsen, 2011; Lalu et al., 2012 - Adapted. 
9.6. 
Record of safety parameters 
Every safety data will be recorded in the participant's medical records and 
will later be transcribed to the company's CRF. The database will be converted to the 
format of tables and sent to statistical advisory. 
9.6.1. Suspension of administration of the investigational product 
If after the first administration there is a suspicion of the occurrence of an 
adverse event that may possibly threaten the participant's life, the Medical 
Investigator of the ADORE-DH project should judge whether the treatment should be 
discontinued or suspended indefinitely.  Among such events, it may be considered 
(not restricted to): 
•
Systemic Inflammatory Response Syndrome (SIRS);
•
Anaphylactic shock or allergic reaction;
•
Significant reduction in total platelet count and granulocytic cells
(neutrophils, eosinophils and basophils);

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• Prolongation of prothrombin (TP) time and activated partial 
thromboplastin (TTPa); 
The suspension of the administration to a participant due to the 
occurrence of one of the events mentioned above must be informed to Sponsor 
within a maximum period of 24 hours and notified to the Research Ethics Committee.  
 The safety assessment should be carried out at each visit in which the 
drug of the study takes place.                                                                                                           
 
9.6.2. Study Interruption/Suspension 
Due to the unknown risk related to the frequency and severity of adverse 
reactions involving cellular products, the first clinical studies conducted with these 
products included standards/rules aimed at temporary interruption of the inclusion of 
participants until any condition that put the participant's safety at risk was fully 
evaluated.  
According to the document Considerations for the Design of Early-Phase 
Clinical Trials of Cellular and Gene Therapy Products - Guidance for Industry (FDA, 
2015), these rules called "stopping rules", shall specify a number of adverse events 
or deaths that will lead to the temporary interruption of the study in order to have a 
systematized review of some study criteria such as dose, number of administrations, 
eligibility criteria, mode of administration or manufacture of the investigational 
product. These rules aim to increase the safety of the investigational product in 
relation to the unpredictable risks that will be evaluated, identified and resolved 
during the clinical follow-up of the study.  
For the ADORE-DH study, the following rules (stopping rules) are 
considered decisive in determining the temporary interruption of the study:  
• Death of one of the research participants related to therapy with 
investigational product (necropsy to define the cause of death);   
• Occurrence of one or more serious adverse events, such as SIRS, 
pulmonary thromboembolism, vascular thrombosis, acute myocardial 
infarction, hemorrhage, stroke, among others, in more than one 
participant with a proven relationship with the investigational product 
and that at the investigator's discretion may jeopardize the safety of the 
other participants.  

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Any occurrences related to the events reported above, shall be informed 
to Sponsor within a maximum of 24 hours and reported to the Research Ethics 
Committee (CEP).  
 
9.7. 
Providing data and tracking of participants 
For all adverse events, the Investigator is obliged to obtain and provide 
information, in addition to reporting it in the medical records and CRF, in accordance 
with what is requested by the clinical monitor and pharmacovigilance. In general, this 
includes a sufficiently detailed description of the adverse event to allow a thorough 
medical evaluation of the case and determination of possible causality. 
In the event of the death of a participant, the causa mortis (cause of death) 
should be reported in the initial notification, when known, or later with the follow-up of 
the causa mortis. A copy of the death certificate should be forwarded to 
Pharmacovigilance.  
The Investigator shall ensure that information about such cases, reported 
by telephone or by any other means, and the information recorded in the clinical 
study form is accurate and consistent. 
In case of possible damage to the participant's health, proven by the 
investigational products used in the study, the participant will be indemnified in 
accordance with current legislation. In addition, in case of need for medical treatment 
with or without the need for hospitalization, it will be provided by the institution that 
assists it. Pre-planned surgical treatments or procedures should be recorded in the 
initial documentation during the protocol period and for each individual in particular. 
 
9.7.1. Contact with the Sponsor 
The names and contact telephone numbers of representatives of Cellavita 
Pesquisa Científica LTDA, the Principal Investigator, among others, are listed in item 
III of this protocol and will be made available to participants. 
 

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10. ETHICAL AND REGULATORY CONSIDERATIONS 
This Protocol will be conducted in accordance with the guidelines of the 
International Conference on Harmonization - ICH for Good Clinical Practices and 
Document of the Americas, as well as national and international legislation. 
The Research Center with its Investigators, sub-investigators, study 
coordinators and internal monitors declare that the protocol and the Informed 
Consent Form will be conducted in accordance with current ICH GCP and in 
accordance with applicable local regulations (Resolution No. 466 of December 12, 
2012, Resolution No. 251 of August 7, 1997) of the CNS-MS. 
 
10.1.  Declaration of the Americas and Regulation 
The study will be conducted in accordance with resolutions 466/12 and 
251/97 of the National Health Council/MS, respecting mainly the participant and the 
Good Clinical Practices/Document of the Americas. 
 
10.2.  Belmonte Communication 
The study will comply with the guidelines of ethical conduct of the 
Belmonte Communication, which has 3 basic principles: 
a) Respect; 
b) Beneficence; 
c) Justice. 
 
10.3. Informed Consent Form (ICF) and Image Authorization Term 
The Investigator will protect the integrity of the participants by following all 
applicable regulations. These regulations are made available upon Sponsor's 
request. The ICF used during the consent-obtainment process must be reviewed by 
Sponsor, approved by CEP and made available for inspection. 
Before any procedure required by the protocol is performed, the participant 
must: 
• 
Be informed of all relevant aspects of the study and the elements of  
informed consent.  
• 
Have enough time to resolve doubts and think about the decision to 
participate. 

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• 
Voluntarily agree to participate in the study.  
• 
Sign and date an informed consent form approved by the CEP. 
 
The Image Authorization Term must be signed for participants who allow 
them to be filmed for scientific purposes. The same standards of Good Clinical 
Practice so followed for obtaining the ICF will apply to this term as well. 
 
10.4. Risks and benefits 
The risks involving the drugs in the study are: rejection of the administered 
cells, susceptibility to opportunistic diseases, grafting of cells in an unwanted place, 
unwanted biological effect (in vivo differentiation in unwanted cell types), toxicity 
(infusion 
or 
systemic) 
(symptoms: 
transient 
fever, 
bronchospasm 
and/or 
laryngospasm, chills, diarrhea, dyspnea, headache, facial edema, glottis and/or 
larynx, fever, hemoglobin, hypotension, nausea, itching, facial flushing, abnormal 
bleeding, sweating, tachycardia, dizziness, hives and vomiting), toxicity to DMSO 
(symptoms: cough, flushing, rash, chest tightening and wheezing, nausea and 
vomiting, cardiovascular instability), formation of neoplasms (malignant or benign), 
transmission of diseases, reactivation of latent viruses, unwanted immune response, 
cellular contamination (with unwanted cells, components of the culture media or 
chemical compounds), mixture of autologous material of the patient, cardiac, 
vascular, renal, neurological, pulmonary, hematological or hepatic dysfunctions 
(malignant or benign).  
When applicable, adverse events will be minimized and if they evolve it 
will be the responsibility of the Sponsor of the study to follow-up the participant until 
the solution thereof. 
The potential benefits of the investigational product are the reduction of 
neuronal loss and the stimulation of neurogenesis of both endogenous and newly 
transplanted cells, activating a neuroprotective environment that is able to integrate 
new cells and replace dead neural cells or in the process of apoptosis. Therefore, cell 
therapy could be able to delay the onset or course of pathology, which would 
represent a major advance for these patients (Fink et al., 2015).  
Based on these data and due to the devastating and fatal nature of the 
disease, it is possible to observe that the benefits presented in this study outweigh 
the possible risks involved.  
 

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10.5. Preserving the identity of research participants  
In the process of maintaining the right of the participants' privacy, each 
participant will be codified at the time of inclusion and this code should be used in the 
study documentation.  
 
10.6. Post-study drug supply 
Sponsor understands and is aware of the foregoing in item III.3.d of CNS 
Resolution N. 466/2012 that all participants are assured, at the end of the study, to 
get free and indefinite access to the best therapeutic methods that prove effective. 
Sponsor is also aware of sub-item d1 that access will be guaranteed in the interval 
between the end of individual participation and the end of the study, and in this case, 
this warranty can be given through an extension study, according to the duly justified 
analysis of the participant's attending physician. 
The benefit weighting of the investigational product is done in two distinct 
ways: collectively or individually. The individual benefit analysis is performed when 
the participant terminates his/her participation in the study, and not when the 
research is completed. If the investigational product has proved beneficial to the 
individual, the product must be supplied for as long as necessary (guarantee of 
continuity). The definition of the individual benefit is not the exclusive prerogative of 
the study physician and can also be performed by the participant's personal 
physician (assistant). The collective benefit is that defined in interim or final analyses, 
when it is possible to conclude whether the investigational product proved beneficial, 
or not, to the experimental group. In this case, the supply of the investigational 
product should also extend to the control group.  
Thus, in the event of individual benefit, Sponsor shall ensure the provision 
of the investigational product free of charge, if efficacy is demonstrated, and this is a 
weighting of the study physician or personal physician. Furthermore, in the case of 
collective benefit, Sponsor shall ensure, free of charge, the investigational product to 
all participants of the research if collective benefit is observed, identified in interim 
analysis or at the end of the study. Therefore, Sponsor undertakes, before the 
Brazilian regulatory authorities, to ensure access to the investigational product of the 
study to all participants who participate in this study (for both discontinued or non-
discontinued participants), according to the commitment established in the Informed 

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Consent Form, and according to the judgment/prescription of the Investigator and/or 
clinical team. 
Access to the study medication will be ensured for as long as necessary at 
the discretion of the physician, or in case the treatment is replaced or presents any 
safety-related problems.  
 
10.7. Declaration of interest 
The Research Center with its Investigators and sub-investigators declare 
absence of any conflict of interest. 
 
10.8. Ethics and publication policy 
Sponsor's policy is to publish or otherwise communicate the results of its 
clinical case-checking and exploratory studies, whatever the evolution, for marketed 
products, compound(s) or research product(s) subsequently approved for 
commercialization.  
Clinical hypothesis test studies are those that aim to provide significant 
results through the analysis of pre-specified questions, using statistically valid 
predefined plans for data analysis, thus providing strong evidence of safety and/or 
efficacy to corroborate their claims about the products. 
On the other hand, exploratory studies serve to determine the direction of 
possible future studies. They have significant statistical limitations, provide only 
preliminary information about a disease, condition, or product, and are not designed 
to provide final conclusions about product claims. 
Therefore, in accordance with Resolution 466/12, Sponsor declares that 
the search results will be made public, whether favorable or not. 

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11. PROTOCOL CHANGES 
 
11.1. Amendments 
Any change in the study plan requires an amendment to the protocol. The 
Investigator shall not make any changes to the study without the approval of the CEP 
and Sponsor, except where necessary to eliminate immediate obvious risks to 
participants. An amendment to the protocol to eliminate an immediate obvious risk to 
participants can be promptly implemented, but the change must then be documented 
in an amendment, informed to the CEP within 5 working days, and forwarded to the 
regulatory agency within the required time frame. All amendments to the protocol 
must be analyzed and approved, following the same process as the original protocol. 
 
11.2. Amendment submission  
The amendments, in the context of RDC 09/2015, are defined as any 
changes made to the clinical protocol, whether substantial or not, and it is at 
Sponsor's discretion to evaluate in which of these categories it will fit and its impact 
on clinical development.  
Substantial amendments are considered those that interfere with the 
safety, physical or mental integrity of research participants, as well as significant 
changes in the scientific value of the clinical trial protocol, such as the change from a 
placebo comparator to an active comparator, insertion of additional experimental 
arms, or changes in the statistical analysis plan. On the other hand, non-substantial 
amendments are those that do not entail alterations relevant to the scientific value of 
the protocol, such as small clarifications, spelling correction, among others.  
All amendments (substantial or non-substantial) must be submitted to the 
country CEP at the same time. However, substantial amendments must wait for both 
ethical assessment and manifestation of CONEP to be implemented to the protocol 
already presented, while non-substantial ones can be promptly implemented, being 
only described as part of the annual report of the clinical trial. 
 
 
11.3. Deviations and protocol violations 
 
Deviation from protocol: any lack of compliance with the procedures or 
requirements defined in the version of the protocol approved by the Research Ethics 

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Committee (CEP) without major implications for the integrity of the study, the quality 
of the data or the rights and safety of the participants.  
 
Violation of protocol: deviation from the protocol that may affect the quality of the 
data, that compromises the integrity of the study or that may affect the safety or 
rights of participants. 
In general, a significant deviation from the protocol is considered as a violation of the 
protocol, while a minor deviation is considered as a deviation from the protocol. 
Any deviation from the original statistical plan shall be described and 
justified in the protocol and/or final report, if appropriate. Table 06 exemplifies the 
significant deviations from the protocol and the necessary actions and 
documentation. 
 
Table 06. Model of protocol deviations and corrective actions. 
Significant Deviations from the 
Protocol 
Action/Documentation Required 
Some 
Baseline 
procedure 
was 
performed after the administration of the 
medication under study 
The deviation must be notified by the monitor via the 
Protocol Deviations form. In addition, the reason for the 
deviation should be documented in the participant's 
medical records. 
Deviations from inclusion and exclusion 
criteria 
When this type of deviation is found after randomization, 
the study team should be notified to determine whether 
the participant should remain in the study. The reason 
for the deviation should be documented in the 
participant's medical records. 
Variance in The Statistical Test to Be 
Used 
Any deviation from the Statistical Test to be used must 
be thoroughly justified in the final report.  
 
 
 
 
 
 
 
 
 

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12. SUSPENSION, CLOSURE AND COMPLETION OF THE STUDY 
Sponsor may suspend or terminate a study, or part of it, at any time for 
any reason. After the decision of suspension or cancellation, Sponsor shall notify the 
CEP within a maximum of 15 calendar days, except in cases of temporary 
suspension as a security measure, when the period is 7 calendar days from the date 
of suspension. It is emphasized that cancellations under RDC 09/2015 are definitive 
and apply only to clinical trial protocols already initiated, with no possibility of 
subsequent reactivation.  
If the Investigator suspends or terminates the study, he/she shall inform 
Sponsor and CEP immediately and provide them with detailed written information. 
The Investigator will also return to Sponsor all products under investigation, their 
containers and other study materials. At the time of completion of the study, the 
Researcher will provide Sponsor and CEP the final reports and abstracts, as required 
by current regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. QUALITY CONTROL  
Sponsor performs quality control and warranty checks on all clinical 
studies that it sponsors. Before including any participant in this study, the Sponsor 
team and the Investigator review the protocol, the Investigator's Brochure, the CRF's 
and the instructions for its completion, the procedure for obtaining informed consent, 
and the procedure for reporting AEs and SAEs. A qualified Sponsor representative 
will monitor the conduct of the study. During these visits to the centers, the 
information recorded in the CRF's will be compared with the source documents. 
 
 
 
 
 
 

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14. DATA CONTROL AND RECORD MAINTENANCE 
 
14.1. Investigator 
The Investigator will allow monitoring related to the study, audits, CEP 
analysis and regulatory inspections, authorizing direct access to data and source 
documents. 
All information will be recorded in the source documents. CRF's must be 
fully populated and include all required data. All CRF data must be submitted to 
Sponsor during the study and at the end of the study. Remote data capture 
(electronic data capture – EDC - e-CRF) will be used to register and transmit data 
electronically to Sponsor. 
If any Investigator ceases to conduct the study for any reason, he/she 
shall notify Sponsor to discuss an acceptable storage solution. Regulatory agencies 
will be notified with proper documentation. 
An updated statement on the Investigator's form will be on file with the 
Sponsor for any study staff changes reported in the current statement on the 
Investigator's form. 
Investigators must notify the CEP of protocol violations in accordance with 
local and CEP regulatory requirements.  
 
14.2. Sponsor 
E-CRF data is stored in a database and processed electronically. The data 
are reviewed for completeness and logical coherence. Automated validation 
programs identify missing data, discrepant data, and other data inconsistencies. 
Requests for data clarification are sent to the Research Center for resolution. 

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Lupus 2007;16:121-128. 
 

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Sponsor: Cellavita Pesquisa Científica LTDA 
 
Amendment 6 dated February 23, 2021. 
 
 
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