A Phase 1/2a Clinical Trial to Assess Safety of a Single IV Infusion of Autologous Adipose-derived Mesenchymal Stem Cells in Adults With Active Rheumatoid Arthritis
Phase: PHASE1
Conditions: Rheumatoid Arthritis
Sponsor: Hope Biosciences LLC

 
 
The procedures set forth in this protocol are designed to ensure that the Hope Biosciences(s) 
and principal investigator(s) abide by the International Conference on Harmonization (ICH) 
current Good Clinical Practice (cGCP) guidelines, current Good Laboratory Practice (cGLP) 
guidelines, the Declaration of Helsinki, and applicable local regulatory requirements and 
laws in the conduct, evaluation, and documentation of this study. 
 
CONFIDENTIAL 
 
 
CLINICAL STUDY PROTOCOL 
 
A phase 1/2a Clinical Trial to assess safety of a single IV infusion of 
autologous adipose-derived mesenchymal stem cells in adults with active 
Rheumatoid Arthritis 
 
ETHICS AND REGULATORY COMPLIANCE STATEMENT 
 
Current Version and Date: 
V1.4 dated 24Sep2019 
Previous Version and Date: 
V1.3 dated 11Jan2019 
IND Number 
20182263 
ClinicalTrials.gov Link 
https://clinicaltrials.gov/show/NCT03691909 

 
 
Safety of a single IV infusion of HB-adMSCs in RA 
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Version 1.4 
Protocol title: A Phase 1/2a open label study to assess the safety of one single intravenous dose 
of Hope Biosciences’ autologous adipose-derived mesenchymal stem cells in patients with active 
rheumatoid arthritis 
 
Principal Investigator: Amber Khan, MD and Philip A. Waller, MD 
 
Study Coordinator: Emily Birdshead and Bradley Lamach 
Study Type: Interventional 
Population: 12-15 human subjects 
Number of Sites: 
1. Accurate Clinical Research at 2222 Greenhouse Road, Suite 800, Houston, TX 77084 
2. Accurate Clinical Research at 12553 Gulf Freeway, Houston, TX 77034 
 
Study Duration: 18 months 
 
Subject Duration: 12 months 
 
 
1 Introduction 
 
During the last decade, mesenchymal stem cells (MSCs) have been thoroughly studied in 
vitro and in vivo in experimental animal model of autoimmune and inflammatory disorders. They 
play an important role in the treatment of degenerative and autoimmune diseases when injected 
intravenously due to four of their most important characteristics, which have been confirmed in 
vivo: 
 
1. The ability to target sites of inflammation (Dimarino, Caplan, & Bonfield, 2013). 
2. The ability to differentiate into various cell types (Augello & De Bari, 2010). 
3. The ability to stimulate the recovery of injured cells and inhibit inflammation through 
secretion of multiple bioactive molecules (Caplan & Dennis, 2006). 
4. In autologous use, the lack of immunogenicity and the ability to perform 
immunomodulatory functions (Larghero et al., 2009). 
 
The investigational product is autologous adipose-derived culture-expanded mesenchymal stem 
cells (abbreviated as HB-adMSCs) for the treatment of Rheumatoid Arthritis (RA), which 
consists of progressive and persistent inflammation of multiple synovial membranes, causing 
joint pain, stiffness, swelling, and redness, and very often leading to the erosion and destruction 
of bone and cartilage. This disease causes increasing disability and decreases patients’ ability to 
perform daily activities, thus significantly reducing their economic and social quality of life. RA 
is associated with increased mortality and comorbidities (most commonly, cardiovascular 
disease, infections, mental health conditions, and malignancies) (Singh et al., 2016). 

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Patient-derived autologous stem cells present a safe option for RA since these will not induce 
immune rejection and thus multiple treatments are possible without any risk for rejection, which 
may arise from allogeneic stem cell transplantations (Larghero et al., 2009). 
 
MSCs are known for their ability to regulate the immune system and reduce inflammation 
(Dimarino et al., 2013). These also have low immunogenicity due to low expression levels of 
major histocompatibility complex-I (MHC-I) and no expression of MHC-II molecules and 
costimulatory molecules including CD80, CD86 or CD40. MSCs also secrete soluble factors 
such as interleukin-6 and macrophage-colony stimulating factor and suppress the activation and 
proliferation of T and B lymphocytes, and interfere with differentiation, maturation and function 
of dendritic cells. Finally, MSCs release anti-inflammatory and anti-apoptotic molecules and 
hence may protect damaged tissues (Machado Cde, Telles, & Nascimento, 2013). 
 
Recent studies demonstrated that MSC transplantation reduces the severity of collagen- 
induced arthritis (CIA) in mice, which is a model for rheumatoid arthritis (RA) in humans (Yan 
et. al, 2016). MSCs are able to modulate cells from both the innate and adaptive immune systems 
promoting an anti-inflammatory environment, which correlates with remission of symptoms and 
normalized serologic results of inflammatory markers such as C-reactive protein (CRP) and 
erythrocyte sedimentation rate (ESR). These improvements were usually noted within the first 
thirty days post-treatment and were sustained for more than one year (Yan, Cen, & Wang, 2016). 
 
Another group conducted a long-term follow-up (one to three years) of seven lupus patients who 
underwent autologous infusion of stem cells and found that they remained free from active lupus 
and improved continuously after transplantation, without the need for immunosuppressive 
medications (Traynor et al., 2000). Similar to RA, lupus is an autoimmune disease that affects 
multiple organs in the body including muscles and joints. Traynor and colleagues found that 
following stem cells transplantation, levels of T cells diversity were similar to those of healthy 
individuals. This finding provides evidence that stem cells replacement may be beneficial in 
reestablishing tolerance in T cells, thereby decreasing the likelihood of disease reoccurrence and 
flares occurrence, which is one of the limitations of current therapies for autoimmune diseases 
including RA. 
 
Currently, there is no cure for RA. Most treatments will facilitate the occurrence of opportunistic 
infections once the immune system of the patient weakens. Available RA treatments are 
designed to modify or regulate specific mechanisms involved in the proinflammatory cytokine 
overproduction, which plays a key role in inflammatory diseases (Klinker & Wei, 2015). 
 
The rationale for using MSCs for the treatment of autoimmunity was first demonstrated in 
experimental acute encephalomyelitis, a model for multiple sclerosis (Zappia et al., 2005). 
Several other studies evaluate the effects of MSCs injection in models of collagen-induced 
arthritis (Augello, Tasso, Negrini, Cancedda, & Pennesi, 2007) or autoimmune type 1 diabetes 
(Fiorina et al., 2009). Our rationale for treating RA patients with HB-adMSCs is based on 
previous evidence of MSCs’ ability to regulate the immune system and replace the damaged cell 
population (Wang, Qu, & Zhao, 2012). We hypothesize that HB-adMSCs can reprogram the 
mature, long-lived, and auto-reactive immune cells to generate a new, properly functioning 
immune system. 

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Accumulating evidence in the published literature showed a safe margin of adipose derived- 
mesenchymal stem cells IV infusion(s) in various diseases such as amyotrophic lateral sclerosis 
(Staff et al., 2016), psoriasis vulgaris and psoriatic arthritic (De Jesus et al., 2016), severe 
osteoarthritis of the knee (Jo et al., 2014; Pers et al., 2016), bone non-union and non-healing 
chronic wounds with no success to conventional therapies (Veriter et al., 2015), spinal cord 
injury (Hur et al., 2016), pregnancy outcome with Crohn’s perianal fistula (Sanz-Baro et al., 
2015) or Crohn’s fistula per se (Cho et al., 2015; Garcia-Olmo et al., 2005), and autoimmune 
disease (Ra et al., 2011). Furthermore, we recently, through an FDA compassionate use 
authorization, provided multiple (7) doses of HB-adMSCs (2x108) to a patient with autoimmune 
thrombocytopenic purpura. No adverse reactions from the administrations were observed. 
Additionally, in a hybrid pharmacology/toxicology study in TBI animals with single and 
multiple IV injections, no safety concerns were observed. Together these results serve as 
evidence of an established, safe profile for clinical use of HB-adMSCs with IV administration. 
 
2 Name and Description of the Investigational Product 
 
Name: Hope Biosciences’ human autologous adipose-derived mesenchymal stem cells (HB- 
adMSCs). 
 
Description: HB-adMSCs have spindle shape and fibroblast-like morphology with positive cell 
surface markers of CD73, CD90, CD29 and CD44. HB-adMSCs do not express hematopoietic 
markers such as CD31, CD34, CD45, or HLA DR. HB-adMSCs can be differentiated into multi- 
lineages under conditions that are selectively favorable for adipogenic, chondrogenic and 
osteogenic differentiation. 
 
Methods: Subjects are tested for human immunodeficiency virus (HIV), hepatitis B virus (HBV), 
hepatitis C virus (HCV), and syphilis (RPR); to qualify for participation in the study, each of 
these tests must be negative with the exception to positive test for antibodies to hepatitis arising 
from having been vaccinated. Each donor undergoes a fat extraction (~ 10cc) at a licensed plastic 
surgeon via mini liposuction from the abdominal adipose tissues. Once arrived at Hope 
Biosciences’ manufacturing facility, the adipose-derived mesenchymal stem cells are harvested 
and cultured for at least three weeks in Hope Biosciences proprietary culture medium. 
 
Intended Use: HB-adMSCs are an autologous use via IV administration (2x108 cells) for 
treatment of active RA. 
 
3 Dose Rationale 
 
In pre-clinical studies, we have tested doses in rats from 1x106 cells to multiple injections of 
3x106 cells. The FDA reference weight for a rat is 0.15 kg, resulting in a dose(s) of 6.66x106 
cells/kg to 2x107 cells/kg. For humans, we will use a dose of 2x108 cells. Based upon a reference 
weight of 60 kg, this results in a dose of 3.33x106 cells/kg. The dose will not be altered based on 
weight because we have not seen any negative effects in rats, and for a human to approach the 
lowest rat dose, the patient would need to weigh 30 kg or less. Thus, based upon the safety 
profile of multiple doses 3x106 cells in a rat, we will evaluate the safety of a low dose (2x108 
cells) of HB-adMSCs in humans. 

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4 Study Objectives 
 
The overall objective of this study is to evaluate the safety profile of a single IV infusion of 
autologous adipose-derived mesenchymal stem cells (HB-adMSCs) in subjects with clinical 
diagnosis of RA. The primary endpoint of this study is to measure the number and frequency of 
adverse event(s) and/or severe adverse event(s) throughout the study duration. The second 
endpoint of this study is to evaluate the ability of HB-adMSCs to alter RA-related inflammation 
via measuring levels of Tumor Necrosis Factor alpha (TNF-a), Interleukin-6 (IL-6), C-Reactive 
Protein (CRP), and Erythrocyte Sedimentation Rate (ESR) after a single infusion of autologous 
HB-adMSCs for up to 12-month post-infusion. 
 
 
5 Target population 
Patients who have active RA and are confirmed by the following criteria: 
Inclusion criteria: 
- 
Adult male or female between the ages of 18 and 65 
- 
Patients have active RA as confirmed by the following criteria: 
• ≥ 6 swollen joints and ≥ 6 tender joints at screening (68-joint count) 
• Abnormal CRP result OR abnormal ESR result at screening. Abnormal CRP result at 
screening OR abnormal ESR defined as: 
• CRP > 4.9 mg/L or ESR > 10mm/hr for men, > 20mm/hr for women 
- 
Patients without current established treatment, or if being treated, patients who are on a 
stable dose of RA therapy regimen for ≥ 4 weeks prior to screening. 
Exclusion criteria: 
- 
Inability to understand and provide signed informed consent 
- 
Pregnancy, lactation, or, if female of childbearing potential, positive serum β-hCG at 
baseline. 
- 
Women of childbearing potential (WOCBP) and men (if their sexual partners are 
WOCBP) must use 1 effective form of birth control throughout the study period. Highly 
effective methods of birth control include true sexual abstinence (defined as refraining 
from intercourse during the entire period of risk), surgery (occlusion bilateral tubal 
ligation, vasectomized partner), hormonal contraceptives associated with inhibition of 
ovulation (oral, injectable, implantable patch, or intravaginal), intrauterine device (IUD), 
or intrauterine hormone-releasing system (IUS). 
- 
Uncontrolled systemic illness, including, but not limited to: hypertension (systolic >150 
mm Hg or diastolic >95 mm Hg); diabetes; renal, hepatic, or cardiac failure or any 
laboratory abnormality that poses a safety risk to the subject such as: 
• 
Hemoglobin ≤8.5 g/dL 
• 
White blood cells (WBCs) ≤3,500/mm3 (3.5G/L) 
• 
Any other illness which, in the opinion of the investigator, characterizes the 
subject as not being a good candidate for the study 

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Office Visit 
Follow-up 
Day 1, Weeks 4, 
 
 
 
- 
Currently diagnosed with any malignant neoplasm. Any patient who was successfully 
treated for cancer and has been disease-free, with no recurrence, for at least 5 years, will 
be considered. 
- 
Participation in another study with an investigational drug or device within 4 weeks prior 
to treatment or 5 half-lives of the investigational product used (whichever is longer). 
- 
Positive results of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), hepatitis B core antibody (HBcAb), hepatitis C antibody (HCV Ab), and/or 
human immunodeficiency virus antibody (HIV Ab) tests at screening (excluding patients 
who are tested positive for HBsAb alone due to a hepatitis B vaccination). 
- 
Positive history of Treponema pallidum. 
 
 
6 Study Design 
 
This is a Phase 1/2a single arm open label single dose study in subjects with Rheumatoid 
Arthritis (RA). 12-15 patients will be enrolled for the study. All subjects will receive a single IV 
administration of 2x108 autologous adipose-derived mesenchymal stem cells. Baseline laboratory 
data will be collected prior to infusion; follow up data will be compared against baseline at 1, 3, 
6 and 12 months. Joint Assessment 68 will be administered at 1, 3, 6 and 12 months. 
 
Figure 1 Study Flow 
Figure 1 Study Design 
 

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Table 1 Proposed Schedule of Procedures and Assessments for the Study 
 
Assessments 
Screening 
Intervention 
Day 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
26 
Wk 
52 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Window 
Up to 28 
days 
0 
0 
0 
±1d 
±3d 
±3d 
±3d 
±3d 
±3d 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
x 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
x 
 
 
 
 
 
 
 
 
 
Prior / Concomitant 
medication review 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs: BP, HR, RR, 
Temp 
x 
 
x 
x 
 
x 
 
x 
x 
x 
Height* and Weight 
x* 
 
x 
x 
 
x 
 
x 
x 
x 
Physical Examination* 
x 
 
 
 
 
x*  
x* 
x* 
x* 
CBC with Differential 
x 
 
x 
 
 
x 
 
x 
x 
x 
ESR 
x 
 
x 
 
 
x 
 
x 
x 
x 
PT/INR 
x 
 
x 
 
 
x 
 
x 
x 
x 
Comprehensive Metabolic 
Profile* 
x 
 
x 
 
 
x 
 
x 
x 
x 
CRP 
x 
 
x 
 
 
x 
 
x 
x 
x 
TNF-a 
 
 
x 
 
 
x 
 
x 
x 
x 
Il-6 
 
 
x 
 
 
x 
 
x 
x 
x 
Urinalysis 
x 
 
x 
 
 
x 
 
x 
x 
x 
Pregnancy Test (B-hCG)* 
x 
 
x* 
 
 
x*  
x* 
x* 
x* 
STD panel* 
x 
 
 
 
 
 
 
 
 
 
Joint Count 68 
x 
 
x 
 
 
x 
 
x 
x 
x 
Fat Extraction 
 
x 
 
 
 
 
 
 
 
 
Administration of 
Investigational Product 
 
 
x 
 
 
 
 
 
 
 
Telephone Encounter 
 
 
 
 
x 
 
x 
 
 
 
Adverse Event Monitoring 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
TOTAL 
 
 
 
 
 
 
 
 
 
 
Intervention 1: Fat Extraction 
Intervention 2: Infusion 
Height: only to be recorded at Screening 
STD Panel: To include HIV, RPR, HBV, HCV 
Physical Examination*: A limited Physical examination to follow up any changes. Symptom driven. 
Telephone Encounters: Will be performed at weeks 1 and 8, will include concomitant medications review and AE monitoring. 
Comprehensive Metabolic Profile: * Protein, Albumin, Bilirubin, Urea Nitrogen, Aspartate aminotransferase, Alanine aminotransferase, 
Potassium, Sodium, Creatinine, Globulin, Albumin/Globulin, Carbon dioxide, Calcium, Glucose, Urea Nitrogen, Alkaline Phosphatase, 
Chloride. 
Pregnancy Test (B-hCG): Only in women of childbearing potential. Serum test is to be done at Screening, urine test is to be done locally at 
other specified timepoints. If a urine test is positive, it will be confirmed by a second test using serum. 

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6.1 Recruitment 
Eligible patients will be invited to participate in the study on a first-come basis, subject to Hope 
Biosciences weekly recruitment goals. Each patient will be informed of the possible risks of the 
procedure and will be required to give informed consent before study-specific procedures can 
proceed. A minimal financial inducement will not be offered, and no subject recruitment 
materials will be used. Each subject will be informed that no personally relevant clinical 
information will be derived from the collected data, and that the only possible benefit to the 
subject is potential reduction in RA inflammation. Medications will be documented, but no 
medications will be held. Each subject’s involvement in the study will be limited to the period 
between signing of the informed consent form (ICF) and end of study visit, which is expected to 
be completed at the end of the follow-up period (week 52). 
 
The electronic health record (EHR) database system at the site(s) will be the main source used to 
identify potentially eligible patients. Study coordinators and/or site recruitment staff will be 
responsible for identifying possible subjects based on the inclusion/exclusion criteria. 
 
Upon completion of site initiation visit(s), subject identification, screening and enrollment will 
occur over approximately 4-6 months. 
 
6.2 Pre-screening and Screening 
Interested subjects will be called and be consented verbally, over the phone, by the clinical 
research coordinator (CRC) to participate in the initial screening. A series of questions will be 
asked over the phone to determine if the potential subject is able to meet the specified inclusion 
and exclusion criteria. Potential subjects who are considered eligible based on the phone screen 
will be brought in for in-person screening visit at which time, lab tests will be conducted as 
described in the inclusion/exclusion criteria section of the protocol. Written consent will be 
obtained before the screening tests are conducted. Results of the lab tests will determine final 
eligibility and will be communicated to the patient prior to the intervention phase. Patients will 
not be considered enrolled in the study until the intervention phase. 
 
6.3 Enrollment log 
The site(s) will be responsible for completing and sending an updated Enrollment Log to Hope 
Biosciences. The log is completed for every subject screened for inclusion in the study. Prior to 
screening, patients will be logged into the sites directory, assigned a personal identification 
number (PID) and given an informed consent to review. Informed consent must be signed prior 
to commencement of any screening procedure. 
 
6.4 Study Intervention Phase 
At the completion of the screening period, subjects meeting all eligibility criteria and who have 
chosen to participate, will undergo fat extraction. Stem cells will be isolated and seeded for 3 to 
6 weeks until the desired number of cells is reached. Infusion will take place at 3-6 weeks after 
fat extraction. 
Following the infusion, patients will be monitored by checking respiration rate, blood pressure, 
pulse and temperature, as well as monitoring for any signs of adverse events at 15 and 30 

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minutes, followed by every 30 minutes thereafter for a period totaling 4 hours post infusion. 
During that four-hour period, patients may be ambulatory and may eat or drink fluids without 
restriction. 
 
6.5 Allocation to Interventional Group 
Patients will be assigned subject numbers as soon as they are screened. Baseline data from 
intervention 2 laboratory results of each subject serves as a control for future testing results while 
on study. 
 
6.6 Follow Up Phase 
The study follow-up period will be over 12 months post infusion, starting 24 hours (Day 1) after 
the infusion, followed by weeks 1, 4, 8, 12, 26 and 52. The length of the follow-up period may 
be extended if an adverse event arises and continues on or after week 52. Visits at weeks 1 and 8 
will be conducted by phone screen where the patient will respond to a questionnaire. Visits at 
day one, weeks 4, 12, 26 and 52 will be conducted at the trial site and will include 68 joint 
assessment, sample collection for laboratory evaluation and patient questionnaire completion 
(see CRF). 
 
6.4 Outcome Measures 
Primary Outcome Measures (Safety) 
The primary endpoint measures of this study are the number and frequency of adverse event(s), 
and/or severe adverse event(s) and/or secondary organ injury (as defined by creatinine for renal 
function, liver enzymes such as AST, ALT for liver damage and CBC to assess bone marrow 
failure) throughout the study duration. 
 
Secondary Outcome Measures 
The secondary endpoint measures for this study include the following secondary functional 
outcomes to evaluate for improvement following treatment with HB-adMSCs: 
o Joint Count 68 (reduction in number both tender and swollen), 
o ESR (static or reduced), 
o CRP (static or reduced), 
o TNFα (static or reduced), 
o IL-6 (static levels or reduced) 
 
 
7 Procedures for study closure: 
 
7.1 Routine study close-out 
The study will end when Hope Biosciences has obtained all data necessary to complete its 
studies of the test product. Study close-out will follow Hope Biosciences standard procedures 
and may include, but is not limited to, review of regulatory documents, collection of completed 
case report forms, reconciliation of study records, removal or destruction of ancillary study 
supplies, and informing the Investigator of remaining obligations (e.g., record retention, final 
report submission to the IRB, financial disclosure updates, etc.). 

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7.2 Suspension or premature termination of the study 
This study may prematurely terminate at any time because of a regulatory authority decision, a 
change in opinion of the IRB, or at the discretion of the Investigator or Hope Biosciences. If this 
trial is temporarily suspended or prematurely discontinued, Hope Biosciences will promptly 
notify the Investigator(s) and provide instructions. If the study is temporarily suspended, Hope 
Biosciences will provide guidance on timing and procedures for resuming the study. If the study 
is prematurely discontinued, all study materials must be collected, and all study forms completed 
to the extent possible. All such materials must be returned to Hope Biosciences upon request. 
 
8 Study Evaluations and Measurements 
 
8.1 Medical Record Review 
Variables that will be recorded from the medical chart (paper or electronic) will include Date of 
birth, Height, Weight, Any history of disease, and Immunization record (if needed). 
 
8.2 Physical Examination & Joint Assessment 
A complete physical examination (head, eyes, ears, nose, throat, heart, lungs, abdomen, skin, 
cervical and axillary lymph nodes, neurological, and musculoskeletal systems) will be performed 
at screening and all subsequent visits excluding fat extraction, infusion and day 1. 
 
Symptom-driven physical examinations will be performed as clinically indicated at any study 
visit. All changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. AE’s will be graded, with defined acceptability 
criteria; standardized classification of AE’s will be conducted using the Common Terminology 
Criteria for Adverse Events (CTCAE V5.0). 
 
At screening and all subsequent visits (except fat extraction, infusion and day 1), counts of 
tender and swollen joints out of 68 selected joints will be performed using the 2010 ACR and 
EULAR classification criteria. Counts will be performed by a trained and qualified joint assessor 
using standardized techniques recommended by EULAR. For each patient, the same joint 
evaluator will be used at all visits if at all possible. 
 
If due to any reason a joint is unevaluable, the joint will be recorded as such on the CRF. If this 
is due to a previous amputation, the joint will automatically be recorded as unevaluable for the 
remainder of the study. 
 
8.3 Vital Signs 
Vital signs of weight, temperature, blood pressure, pulse and respiration rate will be taken at 
every visit except for height, which will only be measured at screening. 
During the infusion, temperature, blood pressure, pulse, and respiration rate will be measured at 
minute 15, 30 and 60. Following the infusion, patients will be monitored by checking respiration 
rate, blood pressure, pulse and temperature, as well as monitoring for any signs of adverse events 
every 30 minutes for a period totaling 4 hours post infusion. 

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8.4 Laboratory Evaluations 
Blood sampling will be performed for Hematology Profile (CBC with differential), ESR, 
Comprehensive Metabolic Profile, IL-6, TNF-a, CRP, Serum ß-hCG* , Urinalysis Complete, 
PT/INR, and serum pregnancy tests for all female subjects without menopause. 
 
8.5 Safety Evaluations 
Safety will be assessed by adverse event (AE) reporting. Any assessment result that deviates from 
what is considered normal will be reported. Hope Biosciences will be responsible for determining 
whether an AE is related to the investigational product or not. These assessments include physical 
examinations, vital signs, and clinical laboratory values. 
 
AE’s will be graded, with defined acceptability criteria; standardized classification of AE’s will 
be conducted using the Common Terminology Criteria for Adverse Events (CTCAE V4.03). 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
The safety endpoints of this study are Incidence of AEs, serious AEs (SAEs), secondary organ 
injury, Clinically significant changes in laboratory values, vital signs and physical examination 
results. 
 
9 Study alteration rules 
 
If any of the following events listed below occur, administration of the study drug will be 
immediately suspended. The Data Monitoring Committee (DMC) will meet to review the 
incident and its etiology. The DMC determine if it is likely related to the drug, the infusion or 
unrelated. If the DMC determines the SAE is unlikely or unrelated to the drug, the study will be 
continued. If the SAE appears to be definitely drug related, the study will be stopped. If the SAE 
is probably or possibly linked to the drug, the DMC will determine the risk to future patients and 
decide if the study should proceed or be stopped. 
• 
Death in any subject 
• 
Unexpected life-threatening event in any subject 
• 
Any unexpected SAE 
• 
Three (3) or more of the same Grade 3 or higher AEs (judged by the investigator, medical 
monitor or sponsor), including infusion site reactions 
• 
Any event which, in the opinion of the investigator, medical monitor or sponsor, 
contraindicates further dosing of additional subjects 
 
After such review, resumption of dosing may be considered, including consideration for any 
prophylactic interventions (e.g. antihistamines or corticosteroids for injection site reactions). 
 
9.1 Dose Step-down Rules 
There will be no dose step-down rules. 
 
9.2 Infusion Stopping Rules 
In the event of an infusion-related reaction, the rate of infusion may be adjusted. If any study 
product-induced hypersensitivity reactions occur, the administration of the IV infusion will be 

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transiently discontinued. If symptoms improve within 30 minutes, the IV infusion should be re- 
administered at the former rate of infusion, otherwise the infusion can continue at 50% of the 
previous rate upon improvement. Patients who develop evidence of severe reactions, especially 
severe dyspnea, bronchospasm or hypoxia must have the infusion interrupted immediately. 
Table 2 Infusion Adjustment Guidelines 
Severity of Symptoms 
Treatment 
Action with Investigational Product 
Mild infusion reactions include but 
are not limited to: Headache, 
nausea, non-pruritic rash or mild 
hypersensitivity (reasons including 
localized cutaneous reactions, mild 
pruritus, flushing, rash, dizziness or 
≤20 mmHg change in systolic blood 
pressure from pre-infusion 
measurement 
Mild infusion reactions should be 
evaluated by the investigator and 
may result in restarting study 
product infusion after treatment 
with normal saline, 
diphenhydramine, and/ or 
acetaminophen at the discretion of 
the investigator 
Stop IV infusion immediately. 
Based on investigator’s judgement, 
choose the most appropriate 
action(s) from the options below: 
• Permanently discontinue IV 
infusion 
• Treat the subject as indicated in 
Section 0 and in combinations 
decided by investigator 
discretion 
• Resume IV infusion at no more 
than half the planned infusion 
rate 
Moderate hypersensitivity reactions 
including but limited to: 
generalized rash or urticaria, 
palpitations, chest discomfort, 
shortness of breath, hypo- or 
hypertension with > 20 mmHg 
change in systolic BP from pre- 
infusion measurement 
Moderate infusion reactions should 
be evaluated by the investigator and 
may require treatment with normal 
saline, diphenhydramine, 
acetaminophen and/or IV 
corticosteroids at the discretion of 
the investigator 
Stop IV infusion immediately. 
Based on investigator’s judgement, 
choose the most appropriate 
action(s) from the options below: 
• Permanently discontinue IV 
infusion 
• Treat the subject as indicated in 
Section 0 and in combinations 
decided by investigator 
discretion 
• Do not resume current 
infusion 
Severe hypersensitivity reactions 
including, but not limited to: Any 
of the above reactions plus fever 
with rigors, hypo- or hypertension 
with ≥ 40 mmHg change in systolic 
BP from pre-infusion 
measurements, signs of end organ 
dysfunction such as dyspnea, 
bronchospasm or hypoxia, 
symptomatic hypotension 
hypotonia, syncope, incontinence, 
seizure, wheezing, angioedema or 
stridor 
OR 
Any life-threatening condition 
defined as a reaction that is life 
threatening and requires pressor 
and/or ventilator support or shock 
associated with acidemia and 
impairing vital organ function due 
to tissue hypoperfusion 
Severe infusion reactions should be 
evaluated by the investigator and 
should include the following per the 
investigator’s judgement: 
• Maintain airway, oxygen if 
available 
• Treat subject immediately, for 
example with: 
o Normal saline 
o Epinephrine for 
bronchospasm, hypotension 
unresponsive to IV fluids, or 
angioedema. Dose and route 
as per local standard of care. 
o IV corticosteroids, such as 
hydrocortisone or 
methylprednisolone 
o Diphenhydramine or 
equivalent 
o Acetaminophen or 
equivalent 
• Call emergency medical 
transport for transport to 
Stop IV infusion immediately. 
Based on investigator’s judgement, 
choose the most appropriate 
action(s) from the options below: 
• Permanently discontinue IV 
infusion 
• Treat the subject as indicated in 
Section 0 and in combinations 
decided by investigator 
discretion 
• Do not resume current 
infusion 

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emergency hospital based on 
judgement of the investigator 
 
 
Medicinal products for the treatment of hypersensitivity reactions such as epinephrine 
(adrenaline), anti-histamines and glucocorticoids, must be available for immediate use in the 
event of an infusion-related reaction during administration of study product. 
 
9.3 Early Withdrawal of Patients from Study 
 
Patients who do not meet all of the inclusion criteria or meet one or more of the exclusion criteria 
will not be enrolled, will be considered screen failures and the primary reason for the screen 
failure will be recorded on the Case Report Form (CRF). 
 
Patients may discontinue from the study for any of the following reasons: 
• 
Patient request/withdraw consent 
• 
Non-compliance with study schedule 
• 
Lost to follow-up 
• 
Investigator request 
• 
Sponsor request 
Patients who do not comply with the protocol or who withdraw consent may be replaced. 
Patients are free to withdraw from the study at any time without providing reason(s) for 
withdrawal and without prejudice to further treatment. The reason(s) for withdrawal will be 
documented in the Case Report Form (CRF). 
 
Patients withdrawing from the study will be encouraged to complete the same final evaluations 
as patients completing the study according to this protocol, particularly safety evaluations and 
follow up telephone calls. Reasonable efforts will be made to contact patients who are lost to 
follow-up. These efforts must be documented in the patient’s file. 
 
It is understood by all concerned that an excessive rate of withdrawals can render the trial 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. Should a 
patient decide to discontinue, all efforts by the investigator will be made to complete and report 
the observations as thoroughly as possible. 
 
9.4 Study Termination 
The sponsor has the right to terminate the study at any time in case of SAE(s) or if special 
circumstances concerning the study drug or the company itself occur that makes further 
treatment of patients impossible. In this event, the investigator will be informed of the reason for 
study termination. 
 
10 Data Quality Assurance 
The study site will be responsible for the accuracy of data. Hope Biosciences or its agent may 
periodically conduct monitoring visits to ensure the quality of data collection. 

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11 Statistical Plan 
Primary Analyses: To provide evidence of the safety of HB-adMSCs, the occurrence rates of 
AEs and SAEs on the patients who take HB-adMSCs. 
For the study, control data will be collected from the baseline rates for AEs and SAEs prior to 
infusion, along with the historical occurrence rates of AEs and SAEs for the specific RA drug 
patients are taking. It may not be possible to separate the cause of the AE or SAE. Evaluation 
will be performed to determine if the rate of AEs and SAEs changes, not to determine the exact 
cause of the AEs and SAEs. 
 
AEs and SAEs will be assessed at baseline time point and at each follow-up visit and when AEs 
or SAEs occur. The AEs and SAEs will be summarized as percentages at each time point, 
calculated as a rate of occurrence. 
All enrolled patients will be examined in the safety study. The goal of the study is to examine 
whether there is observed increase in the occurrence rates of AE or SAE after the adding 
treatment of HB-adMSCs to the patients who take the standard RA drugs. 
 
Secondary organ injury will also be studied, factoring in patient history. An increase in the 
different markers described above (Section 0) will necessitate a review of the patient’s medical 
history to determine if this damage was a trend because of RA treatment or due to the application 
of HB-adMSCs. 
 
Secondary Analyses: Joint Count 66/68 will be assessed at various time points (Error! 
Reference source not found.). The initial score, captured at Intervention 2, will serve as the 
baseline for disease. Any improvement from treatment will be the difference from baseline to 
that score at the follow up visits. Each of the markers used are in Table 3, where results are 
broken into 3 categories such as No Change, Minor Change or Major Change. Results will then 
be reported as a percentage of the total, i.e. 10% No Change. This will occur independently for 
every time point and then as a total at the end, to determine if HB-adMSCs result in any 
temporary or permanent changes in the RA scores. 
 
Interim Analysis: All data is subject to analysis throughout the conduct of the trial, including but 
not limited to 4 weeks post infusion, 3 months post infusion, 6 months post infusion, 1 year from 
beginning of trial, and at End of Study time points. 
 
11.1 Sample Size and Statistical Results 
The study will consist of 12 primary patients and 3 alternates for the treatment group. 
Any assessment result that deviates from what is considered normal will be reported. The PI will 
be responsible for determining whether is related to the investigational product or not, if possible. 
These assessments include physical examinations, vital signs, and clinical laboratory values. 
 
12 Statistical Methods 
 
12.1 Safety Analysis 
All subjects entered into the study and exposed to the IV infusion will have detailed information 
collected on AEs, SAEs and secondary organ damage for the overall safety analysis. 

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12.2 Efficacy Analysis 
Efficacy is a secondary endpoint for this study and will be assessed by comparing the levels of 
acute phase reactants (TNF-a, IL-6, CRP and ESR) and Joint Count 66/68 scores. Table 3 below 
lists how changes in the scores will be considered, relative to efficacy. 
 
Table 3 Markers for Efficacy Analysis 
Marker 
No Change 
Minor Change 
Major Change 
Tumor necrosis factor (TNF) (pg/mL) 
<0.3 
0.3 to 0.9 
> 0.9 
Interleukin 6 (IL-6) (pg/mL) 
<1.5 
1.5 to 3.9 
> 3.9 
C-Reactive Protein (CRP) (mg/mL) 
<0.3 
0.3 to 0.49 
> 0.49 
Erythrosedimentation Rate (ESR) 
(mL/hr) 
Male 
<3 
3 to 7 
> 7 
Female 
<4 
4 to 9 
> 10 
Joint Count (# joints - tender and swollen) 
0 to 1 
2 to 5 
> 5 
 
The score has been created with the intention to classify each patient’s response to the 
investigational product (IP), based on the values we believe are representative for each category. 
No Change – would include any level variation that does not necessarily translate into a 
response to the IP. This range gives room enough for periodic fluctuations 
due to normal physiological changes and/or human error or subjective 
interpretation. 
Minor Change – sets the threshold for a change. Its values indicate that a level is great 
enough to be considered a “response” although it is not remarkable. These 
numbers will flag positive changes, that will be considered signs of “true 
effectiveness”, since the range for physiological fluctuations have been 
surpassed. Minor changes accrued with a single dose will also indicate that 
multiple doses (in future trials) might have an improved outcome. 
Major Change – would be the case of a patient (or group of patients) with substantial 
number variation, being translated to the best response to the IP. Although 
these numbers are high, they still fall into a reasonable chance of occurring. 
 
12.3 Subject Population(s) for Analysis 
All subjects that will be used for analysis, baseline data of each subject will serve as control. 
 
8.1.1.1 Data Quality and Accuracy 
The quality and accuracy of the data generated in this trial will be ensured through the use of an 
electronic records database. The CRO will monitor the sites to ensure data is being safely and 
accurately compiled. Following the completion of the trial, an audit may be conducted as 
determined by the Sponsor at that time, digital and original copies of all data will be secured by 
all parties involved according to HIPAA regulations and good data management practices. 

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9 Risk Analysis 
 
1.1 Potential Risks of the Investigational Product and Clinical Investigation 
 
9.1.1 Risks Associated with HB-adMSCs 
The types of risk associated with HB-adMSCs are stated in the Informed Consent Form (See 
ICF) 
 
9.1.2 Minimization of Risks 
Although the risk to subjects participating in the study is anticipated to be minimal, the clinician, 
at his/her discretion, will not collect data from those individuals for whom collection is judged to 
pose an unusually high risk of physical or mental harm or discomfort. 
 
Participation in this study poses moderate risk to study personnel related to potential pathogens 
that may be present in the subject’s specimens which are then expanded during the culture 
process. These risks will be minimized by adherence to the principles of universal precautions 
and by conducting the planned testing on blood from the subject at screening for particular 
pathogens of concern. 
 
Personnel should wear appropriate personal protective equipment to avoid contact of the eyes or 
skin with hazardous materials or products derived from biological sources. 
 
 
9.2 Data Collection and Management 
 
Case Report Forms/Electronic Data Records 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method(s) used. 
 
Original CRFs should not be made available in any form to third parties, except for authorized 
representatives of Hope Biosciences or appropriate regulatory authorities, without written 
permission from Hope Biosciences. 
 
 
It is the PI's responsibility to ensure completion, review, and approval of all CRFs. CRFs must be 
signed by the PI or by an authorized staff member. These signatures serve to attest that the 
information contained on the CRFs is true. At all times, the PI has final personal responsibility 
for the accuracy and authenticity of all clinical and laboratory data entered on the CRFs. 
 
Reports received by the site from the central laboratory should be printed, retained as source 
documentation and signed by the principal investigator, indicating which values are considered 
clinically significant and to be reported as AEs. 
 
9.3 Records Retention 
 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by a patient’s identification number. 

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All study records, source medical records, and logs linking a patient’s name to an identification 
number will be kept in a secure location. Clinical information will not be released without 
written permission of the patient/legal representative, except as specified in the ICF (e.g., 
necessary for monitoring by regulatory authorities or the Sponsor of the clinical study). The 
Investigator must also comply with all applicable privacy regulations (e.g., US Health Insurance 
Portability Accountability Act of 1996). The investigator and the study site will retain the 
essential documents (e.g., source document such as medical records, signed ICF). Essential 
documents should be retained at the study site for at least 15 years following completion of the 
study, or per regulatory obligations if longer, and thereafter destroyed only after agreement with 
the Sponsor. The Sponsor should notify the head of the study site in writing when the study- 
related records are no longer needed. The records should be managed by a responsible person 
appointed by the head of the study site. 
 
13 Safety and Adverse Events 
 
13.1 Definitions 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity throughout the course of the study. Intercurrent illnesses and injuries should be 
considered as adverse events. Abnormal results of diagnostic procedures are considered to be 
adverse events if the abnormality: 
- 
is associated with a serious adverse event 
- 
is associated with clinical signs or symptoms 
- 
leads to additional treatment or to further diagnostic tests 
- 
is considered by the investigator to be of clinical significance 
 
A serious adverse event (SAE) is any AE that is: 
- 
fatal 
- 
life-threatening 
- 
requires or prolongs hospital stay 
- 
results in persistent or significant disability or incapacity 
- 
Important Medical Events (IME): those events that may not result in death, be 
immediately life threatening, or require hospitalization. They may be considered SAE 
when, based upon medical judgement, they may jeopardize the subject and may require 
intervention to prevent one of the other serious outcomes noted above. For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious. (FDA, 21CFR312.32; ICH E2A and ICH E6) 
 
13.2 Intensity of Adverse Event 
The intensity of the AE will be judged base on the following: 
• 
Mild: Awareness of sign(s) or symptom(s) which is/are easily tolerated 
• 
Moderate: Enough discomfort to cause interference with usual activity 
• 
Severe: Incapacitating or causing inability to work or to perform usual activities 
13.3 Causal Relationship of Adverse Event 
Medical judgement will be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge and confounding factors such 

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as concomitant medication, concomitant disease and relevant history. Assessment of causal 
relationship will be recorded in the CRF. 
• 
Probable: Good reason and sufficient documentation to assume a causal relationship 
• 
Possible: A causal relationship is conceivable and cannot be dismissed 
• 
Unlikely: the event is most likely related to etiology other than the trial product 
13.4 Pregnancy 
In the event that a female subject is diagnosed with a pregnancy during the duration of her study 
participation, the outcome of the pregnancy must be followed to completion of the pregnancy. 
Once a female patient has been enrolled into the clinical trial, after having taken study product, 
the investigator must report immediately any study product exposure during pregnancy to the 
sponsor. Study product exposure during pregnancy has to be reported immediately (within 24 
hours) using SAE forms. The outcome of the pregnancy associated with the product exposure 
during pregnancy must be followed up. If the outcome for the pregnancy meets the criteria for an 
AE or SAE, the investigator should follow the procedures for reporting those events. In the case 
of a live birth, the structural integrity of the neonate should be assessed at the time of birth. In the 
event of a termination, the reason(s) for termination should be specified. 
 
13.6 Recording of Adverse Events 
The study investigator is ultimately responsible for the recording, and reporting to the Sponsor, 
unanticipated problems related to the research, which occur during the study. The time period of 
adverse event collection for the study that will be assessed for analysis will be from Visit 2 
(Infusion) to the end of the study (visit 9). The PIs and any staff members involved directly with 
this clinical trial will report any adverse events that occur throughout the entire duration of the 
study. 
 
At each contact with the subject, the investigator will seek information on adverse events by 
specific questioning (see CRF) and, as appropriate, by examination. Information on all adverse 
events will be recorded immediately in the source document, and also in the appropriate adverse 
event module of the Case Report Form (CRF). All clearly related signs, symptoms, and 
abnormal diagnostic procedures results from a single timepoint visit should be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study duration will be recorded. The clinical course of 
each event will be followed until resolution, stabilization, or until it has been determined that the 
study intervention or participation is not the cause. Serious adverse events that are still ongoing 
at the end of the study period will be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study intervention or study participation will be recorded and reported immediately. 
 
13.7 Relationship of AE to Study 
The relationship of each adverse event to the study procedures should be characterized. It is the 
PI’s responsibility to determine whether the AE is related or not to the intervention. In case there 
is a relationship, this shall be classified as definitely related, probably related, or unrelated. 

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13.8 Reporting of Adverse Events and Unanticipated Problems 
The report should be supplied as a narrative, the minimum necessary information to be provided 
at the time of the initial report includes: 
- 
Study identifier 
- 
Study center 
- 
Subject number 
- 
A description of the event 
- 
Date of onset 
13.9 Follow-up report 
- 
Current status 
- 
The reason why the event is classified as 
serious 
- 
Investigator assessment of the association 
between the event and study intervention 
If a SAE has not resolved at the time of the initial report and new information arises that changes 
the investigator’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) should be submitted to 
the sponsor. The investigator is responsible for ensuring that all SAEs are followed until either 
resolved or stable. 
 
9.3.1 Investigator reporting: notifying the study sponsor 
Any study-related unanticipated problem posing risk to subjects or others, and any type of 
serious adverse event, will be reported to Hope Biosciences (Sponsor) by telephone within 24 
hours of the event. To report such events, a Serious Adverse Event (SAE) form will be 
completed by the investigator and electronically faxed to the sponsor within 24 hours to fax 
number: (855) 700 6838. The investigator will keep a copy of this SAE form on file at the study 
site. 
 
Within the following 48 hours, the investigator will provide further information on the Serious 
Adverse Event or the unanticipated problem in the form of a written narrative. This should 
include a copy of the completed Serious Adverse Event form, and any other diagnostic 
information that will assist the understanding of the event. Significant new information on 
ongoing Serious Adverse Events should be provided promptly to Hope Biosciences. 
 
9.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above. At Hope Biosciences, Dr. Jamshid Lotfi, MD 832-405-6059 will be 
responsible for reviewing any reported AEs and SAEs to determine if changes to the study need 
to be made or if the study should be stopped for the protection of patients. 
 
9.4.1 Data Safety Monitoring Board 
An independent data safety monitoring board consisting of a statistician will review safety data 
of this study, along with the other DSMB members 
• 
 After the first 4 patients have concluded the Visit 5 (week 4 post-injection) to ensure that 
no serious adverse reactions are being observed. 
• 
After the completion of the trial (last patient interview on Visit 9 week 52). 

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9.4.1.1 Responsibility for Providing Data 
The responsibility for providing the data in order for the DSMB to perform safety reviews 
will be the responsibility of Hope Biosciences obtaining the data from the EDC vendor. 
 
9.4.1.2 Early Terminations 
All adverse events definitions and the reporting of such events will occur as defined in Section 0. 
Since this is a single injection of drug, early termination will be based upon the occurrence of 
Serious Adverse Event(s) as described in Section 0, or if already treated patients begin 
experiencing serious adverse events, at that point, any untreated patients will be subject to a 
reduced dose (Section 0). After the reduction of dose, if Serious Adverse Event(s) persist, any 
untreated patients will be removed from the trial. 
 
9.4.1.3 Data Quality and Accuracy 
The quality and accuracy of the data generated in this trial will be ensured through the use of an 
electronic records database. The CRO will monitor the sites to ensure data is being safely and 
accurately compiled. Following the completion of the trial, an audit may be conducted as 
determined by the Sponsor at that time, digital and original copies of all data will be secured by 
all parties involved according to HIPAA regulations and good data management practices. 
 
11.7.1.4 Clinical Monitoring 
The CRO will review data to ensure all patients meet the predetermined requirements for 
participation in the trial (Section Error! Reference source not found.). Once patients have been 
enrolled, the CRO will monitor all reports from the clinical site (and any reports from patients’ 
independent doctors that are submitted) for the occurrence of adverse events, data completeness, 
protocol non-compliance and any new relevant information. The CRO monitor is responsible for 
completing a cross-check of source data at the site with what has been entered into EDC with 
every patient screened/enrolled. A Monitoring Visit Report will be completed by the CRO and 
provided to Hope Biosciences within 10 days. 
 
10 Risk Analysis 
 
1.2 
Potential Risks of the Investigational Product and Clinical Investigation 
 
10.1.1 Risks Associated with HB-adMSCs 
The types of risk associated with HB-adMSCs are stated in the Informed Consent Form (See 
ICF) 
 
10.1.2 Minimization of Risks 
Although the risk to subjects participating in the study is anticipated to be minimal, the clinician, 
at his/her discretion, will not collect data from those individuals for whom collection is judged to 
pose an unusually high risk of physical or mental harm or discomfort. 
 
Participation in this study poses moderate risk to study personnel related to potential pathogens 
that may be present in the subject’s specimens which are then expanded during the culture 
process. These risks will be minimized by adherence to the principles of universal precautions 

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and by conducting the planned testing on blood from the subject at screening for particular 
pathogens of concern. 
 
Personnel should wear appropriate personal protective equipment to avoid contact of the eyes or 
skin with hazardous materials or products derived from biological sources. 
 
1.3 
Potential Benefits 
Subjects may benefit from their participation in the study by experiencing a reduction in joint 
inflammation. 
 
11 Investigator Responsibilities 
 
11.1 Site Qualification and Study Oversight 
The PI is responsible for general administration of the study. 
Before the study, the PI must: 
• 
Obtain approval to conduct the study from the study site’s IRB 
• 
Sign the Protocol Signature Page him/herself and have all sub-investigators sign the 
Protocol 001 Signature Page and return it to Hope Biosciences 
• 
Provide financial disclosures to Hope Biosciences for themselves and all sub- 
investigators participating in study conduct, per Title 21CFR 54 
During the study, the PI must ensure that: 
• 
The study is conducted ethically 
• 
Case report forms (CRFs), including Subject ICFs, are provided with each transfer of 
data requiring informed consent 
• 
All other study forms are completed as instructed by Hope Biosciences. 
 
In the case of completion or termination of the study or an Investigator's role in the study, or at 
Hope Biosciences request, all study materials must be returned to Hope Biosciences. 
 
12 Study Administration, Data Handling and Record Keeping 
 
12.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the HIPAA Security Rule 45 CFR Part 160 and Subparts A and C of Part 164; 
the HIPAA Privacy Rule 45 CFR Part 160 and Subparts A and E of Part 164. 
In the event that a subject revokes authorization to collect or use PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vitals status at the end of their scheduled 
study period. 
 
12.2 
Data Collection and Management 
 
Case Report Forms/Electronic Data Records 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method(s) used. 

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Original CRFs should not be made available in any form to third parties, except for authorized 
representatives of Hope Biosciences or appropriate regulatory authorities, without written 
permission from Hope Biosciences. 
 
 
It is the PI's responsibility to ensure completion, review, and approval of all CRFs. CRFs must be 
signed by the PI or by an authorized staff member. These signatures serve to attest that the 
information contained on the CRFs is true. At all times, the PI has final personal responsibility 
for the accuracy and authenticity of all clinical and laboratory data entered on the CRFs. 
 
Reports received by the site from the central laboratory should be printed, retained as source 
documentation and signed by the principal investigator, indicating which values are considered 
clinically significant and to be reported as AEs. 
 
12.3 
Records Retention 
 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by a patient’s identification number. 
All study records, source medical records, and logs linking a patient’s name to an identification 
number will be kept in a secure location. Clinical information will not be released without 
written permission of the patient/legal representative, except as specified in the ICF (e.g., 
necessary for monitoring by regulatory authorities or the Sponsor of the clinical study). The 
Investigator must also comply with all applicable privacy regulations (e.g., US Health Insurance 
Portability Accountability Act of 1996). The investigator and the study site will retain the 
essential documents (e.g., source document such as medical records, signed ICF). Essential 
documents should be retained at the study site for at least 15 years following completion of the 
study, or per regulatory obligations if longer, and thereafter destroyed only after agreement with 
the Sponsor. The Sponsor should notify the head of the study site in writing when the study- 
related records are no longer needed. The records should be managed by a responsible person 
appointed by the head of the study site. 
 
13 Study Monitoring, Auditing, and Inspecting 
 
13.1 
Access to Source Documents 
Hope Biosciences or its agents and appropriate regulatory authorities shall be granted direct 
access to all study-related documents to perform verification that the protocol and all applicable 
current Good Laboratory Practices (cGLPs), Good Clinical Practices (GCPs), and regulations are 
being followed and to confirm that study documents are complete and accurate. It is important 
that Investigator(s) and their relevant personnel be made available during monitoring visits and 
any audits or inspections, and that sufficient time is allotted for the process. 
 
13.2 
Financial Disclosure 
Investigators must provide Hope Biosciences with sufficient, accurate financial information in 
accordance with local regulations to allow Hope Biosciences to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. Investigators 
are responsible for providing information to Hope Biosciences concerning their relevant 

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financial interests during the course of the study and for 1 year after completion of the study. 
Conflicts of interest should be disclosed as required by law. 
 
13.3 
Deviations from the Study Protocol 
An Investigator may not knowingly deviate from the study protocol without prior approval by 
Hope Biosciences unless the deviations are necessary under emergency circumstances to protect 
the rights, safety, or well-being of human subjects or the scientific integrity of the clinical 
investigation. Deviations must be documented and promptly reported to Hope Biosciences and, if 
applicable, to the IRB providing oversight of the study. Protocol deviations may result in 
corrective and preventive actions and/or disqualification of the Investigator. 
 
13.4 
Study Monitoring Plan 
A Study Monitoring Plan will be developed by the CRO and will identify the key risks to 
patients and to data associated with this specific clinical trial. The study will then be monitored 
according to that plan to ensure that it is conducted and documented properly according to the 
protocol, GCP, and all applicable regulatory requirements. 
On-site monitoring visits will be made at appropriate times during the study. Monitors must have 
direct access to source documentation in order to check the completeness, clarity, and 
consistency of the data recorded in the CRF for each subject. 
The Investigator will make available to the monitor source documents and medical records 
necessary to complete CRFs. In addition, the Investigator will work closely with the clinical 
monitor with applicable regulations GCP guidelines. 
 
13.5 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
Sponsor, government regulatory bodies, and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.). The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. infusion rooms, diagnostic laboratories, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable Hope Biosciences compliance and quality 
assurance offices. 
 
14 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and 
international (ICH) standards of Good Clinical Practice, and applicable institutional research 
policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), for formal approval of the study 
conduct. The decision of the EC/IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be provided to the Sponsor before 
commencement of this study. 

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14.1 
Risks 
To our knowledge, there is no known risk associated specifically with HB-adMSCs infusion. The 
one-time fat extraction is a minimally invasive procedure of low risk. Possible risks related to the 
extraction and the infusion include redness, pain or swelling at the injection site. 
 
14.2 
Benefits 
Direct benefits for the subjects may include improvement of their disease (by decreasing 
inflammation and flares) and collateral treatment of concomitant inflammatory conditions due to 
the anti-inflammatory and regenerative properties of MSCs (Wang et al., 2012). Subjects 
enrolled in the study will be contributing to the advancement of science and to future 
investigations regarding stem cells and possible therapeutic applications, including treatment of 
autoimmune diseases, specifically Rheumatoid Arthritis. 
 
14.3 
Informed Consent Process 
All subjects will be given a copy of the IRB-approved ICF to review before their study 
participation begins. The Investigator, or designee, will explain all aspects of the study in lay 
language and answer all of the potential participant’s questions regarding the study. If the 
participant decides to participate in the study, he/she will be asked to sign and date the ICF. 
Subjects who do not elect to participate or who withdraw from the study will be treated without 
prejudice. 
 
For each study patient, written informed consent will be obtained prior to any protocol-related 
activities. As part of this procedure, the Investigator, or designee, must explain orally and in 
writing the nature, duration, and purpose of the study, and the action of the investigational 
product in such a manner that the patient is aware of the inconveniences, or adverse effects that 
may occur. The patient should be informed that he/she may withdraw from the study at any time. 
The Investigator will provide the Sponsor or its representative with a copy of the IRB/IEC- 
approved ICF prior to the start of the study. 
 
14.4 
IRB Review 
Hope Biosciences is required to obtain IRB oversight of the research study. The IRB must be 
provided with Hope Biosciences-approved study protocol. Performance of the study may not 
begin until written evidence of IRB approval has been provided to Hope Biosciences. 
 
The conduct and performance of this study will be in accordance with applicable Hope 
Biosciences and Investigator responsibilities as described in Title 21 CFR 312, subpart D and 
other Good Clinical Practice guidance. 
 
IRB/Ethics Committee oversight will be required as human subjects or data from humans are 
being used. This protocol and the associated informed consent document(s), telephone screen 
questionnaires and other case report forms, as applicable, must be submitted to the IRB for 
review and approval. Performance of the study at a given site may not begin until written 
evidence of IRB oversight has been provided to Hope Biosciences study manager. IRB Review 
and approval must comply with Title 21 CFR 312 Subpart D. 

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14.5 
Confidentiality of Data and Patient Records 
The study institution shall keep all records associated with this study for at least 15 years, as 
specified in Section 12.3. Investigators will keep all records associated with this study for at least 
15 years. 
 
14.6 
Provisions to Protect the Privacy Interests of Participants 
The PI and/or study institution shall provide sufficient information to allow the IRB to evaluate 
the researcher’s provisions to maintain the confidentiality of data. 
and, as needed, provide them appropriate evidence that the conduct of the study is being done in 
accordance 

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