Clinical trial NCT05116540
Conditions: Multiple Sclerosis
Keywords: Mesenchymal Stem Cells MS RRMS stem cells MSCs Relapsing Remitting
Sponsor: Hope Biosciences Stem Cell Research Foundation
Start date: 2021-11-24; Completion date: 2024-06-04
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized Double-Blind Efficacy and safety study of Autologous HB-adMSCs versus placebo for the treatment of Multiple Sclerosis. This study will be for 24 subjects with 6 infusions over a 52 week period. Study participants will continue their established concomitant medications during participation in this investigation.

Detailed description:
Each eligible study subject will receive a total of 6 intravenous infusions of HB-adMSCs or placebo. Study infusions will be administered with the following regimen, Week 0, 4, 8, 16, 24, and 32. There will be one follow-up visit and end of study at week 52.

Arms: arm 1: Adipose derived Mesenchymal stem cells (Autologous) arm 2: Normal Saline
Interventions: intervention 1: HB-adMSCs intervention 2: Placebo
Intervention descriptions: intervention 1: Autologous product intervention 2: Normal Saline

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL  
 
Protocol Number: HBMS01 
 
“A Randomized, Double-Blind, Single Center, Phase 2, Efficacy and Safety Study of 
Autologous HB-adMSCs vs Placebo for the Treatment of Patients with Multiple Sclerosis” 
 
IND Number: 
27633 
Name of Products: 
HB-adMSCs – Hope Biosciences adipose derived 
mesenchymal stem cells.  
or  
Placebo - Sterile Saline Solution 0.9%  
Indication: 
Multiple Sclerosis 
Principal Investigator: 
Djamchid Lotfi, MD  
Email: lotfi99@yahoo.com  
Telephone: (713) 533-1260  
Protocol Version: 
1.0  
Protocol Version Date: 
20/Sept/2021  
 
CONFIDENTIAL 
 
This document and its contents are the property of and confidential to Hope Biosciences Stem 
Cell Research Foundation and Hope Biosciences, LLC. Any unauthorized copying or use of this 
document is prohibited. 
Ethics and Regulatory Compliance Statement 
  
The procedures set forth in this protocol are designed to ensure that the Hope Biosciences Stem 
Cell Foundation, Hope Biosciences, LLC, and principal investigator(s) abide by the International 
Conference on Harmonization (ICH) current Good Clinical Practice (cGCP) guidelines, current 


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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. 
 
Study Summary 
 
Title 
“A Randomized, Double-Blind, Single Center, Phase 2, Efficacy 
and Safety Study of Autologous HB-adMSCs vs Placebo for the 
Treatment of Patients with Multiple Sclerosis” 
Short Title  
“HB-adMSCs vs Placebo for the treatment of Patients with Multiple 
Sclerosis”.  
Protocol Number:  
HBMS01 
Methodology 
Randomized, Double-Blind 
Phase of Development:  2 
Treatment Duration  
32 weeks   
Study Center  
Single Center – Hope Biosciences Stem Cell Research Foundation  
General Objectives 
To assess the efficacy and safety of multiple intravenous infusions 
of HB- adMSCs vs Placebo by improving activities of daily living 
and quality of life in subjects with Multiple Sclerosis. 
Number of Subjects  
24 subjects  
Diagnosis 
Relapsing Remitting Multiple Sclerosis 
Study Product, Dose, 
Route, Regimen.  
Active Product: HB- adMSCs (Hope Biosciences adipose derived 
mesenchymal stem cells)  
Dose: 200 million  
Route: Intravenous  
Regimen: Weeks 0, 4, 8, 16, 24 and 32.  
 
Placebo: Saline Solution 0.9%  
Dose: N/A  
Route: Intravenous  
Regimen: Weeks 0, 4, 8, 16, 24 and 32. 
Duration of 
administration  
1 hour  
Laboratory Samples.  
Screening, Week 0, 24 and 52.  
Visits by Weeks 
Screening  
Week   0 – Infusion 1  
Week   4 – Infusion 2 
Week   8 – Infusion 3 
Week 16 – Infusion 4 
Week 24 – Infusion 5 
Week 32 – Infusion 6 


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Week 42 – Follow Up.  
Week 52 – End of Study  
 
“A Randomized, Double-Blind, Single Center, Phase 2, Efficacy and 
Safety Study of autologous HB-adMSCs vs Placebo for the Treatment of 
Patients with Multiple Sclerosis” 
Objectives  
 
Primary Objective 
 
• To investigate the efficacy of intravenous infusions of HB-adMSCs vs Placebo in patients 
with Multiple Sclerosis as determined by improvements in Multiple Sclerosis Quality of 
Life (MSQOL)-54 Instrument. (Time frame: Baseline to Week 52).  
 
Secondary Objectives 
 
• To evaluate the efficacy of intravenous infusions of HB-adMSCs vs. Placebo in patients 
with Multiple Sclerosis as determined by changes in Expanded Disability Status Scale 
(EDSS) (Time frame: Baseline to Week 52).  
 
• To assess the efficacy of intravenous infusions of HB-adMSCs vs. Placebo in patients 
with Multiple Sclerosis as determined by changes in The Barthel Index (Time frame: 
Baseline to Week 52).  
 
• To determine the efficacy of intravenous infusions of HB-adMSCs vs. Placebo in patients 
with Multiple Sclerosis as determined by changes in 9-Hole Peg Test (Time frame: 
Baseline to Week 52).  
 
• To identify the safety of intravenous infusions of HB-adMSCs vs. Placebo in patients 
with Multiple Sclerosis as determined by changes in Patient Health Questionnaire (PHQ-
9) (Time frame: Baseline to Week 52).  
 
• To assess the safety of intravenous infusions of HB-adMSCs vs. Placebo in patients with 
Multiple Sclerosis as determined by the incidence of adverse events or serious adverse 
events (Time frame: Baseline to Week 52).  
 
 
Endpoints   
 


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Primary Endpoints  
 
The safety and efficacy endpoints of this study will be evaluated by assessing changes from 
Baseline to Weeks 52 in the following:  
 
• Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument. This 54-item questionnaire 
provides 12 subscales, two summary scores, and two extra single-item measures. The 
subscales are physical function, role limits-physical, emotional role restrictions, pain, 
emotional well-being, energy, health perceptions, social function, cognitive function, 
health distress, overall quality of life, and sexual function. 
 
• Incidence of treatment-emergent Adverse Event (TEAEs) and serious Adverse Events 
(SAEs).   
 
• Incidence and risk of AEs of special interest (serious or nonserious), including 
thromboembolic events, peripheral events defined as, thromboembolism of the 
extremities, also infections and hypersensitivities.   
 
• Clinically significant changes in laboratory values, vital signs, weight, and physical 
examination results. 
 
Secondary Endpoints  
 
The safety and efficacy endpoints of this study will be evaluated by identifying changes from 
Baseline to Week 52 in the following:  
 
• Expanded Disability Status Scale (EDSS) 
 
• The Barthel Index 
 
• 9-Hole Peg Test  
 
• Patient Health Questionnaire (PHQ-9) 
 
• Incidence of treatment-emergent Adverse Event (TEAEs) and serious Adverse Events 
(SAEs).   
 
• Incidence and risk of AEs of special interest (serious or nonserious), including 
thromboembolic events, peripheral events defined as, thromboembolism of the 
extremities, also infections and hypersensitivities.  
 


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• Clinically significant changes in laboratory values, vital signs, weight, physical 
examination results and Multiple Sclerosis concomitant medications.  
 
 
Investigational Plan.  
 
This is a randomized, double-blind, single center, phase 2 study to assess efficacy and safety of 
multiple HB-adMSCs vs. Placebo for the treatment of Multiple Sclerosis. The trial includes a 
screening period of up to 4 weeks, a 32-week treatment period, and a safety Follow-up period of 
20 weeks after the last investigational product administration.  
 
This clinical trial will be opened to enroll 24 eligible participants diagnosed with Multiple 
Sclerosis. Patients’ recruitment will be conducted by the study team, if eligible participants are 
identified based on eligibility criteria, a screening visit will be scheduled. Informed consent form 
will be given to the study participants and signed before any study procedures. Informed consent 
form will include information about the clinical trial and some aspects should be considered 
during this process.  
 
• Principal investigator and/or study team will make sure the participant was alert, and able 
to read and understand the language in the consent form.  
• Principal investigator and/or study team will make sure the participant takes ample time 
to carefully read the consent form.  
• Principal investigator and/or study team will make sure the consent form is carefully 
explained to the participant and any questions or concerns are addressed before signing 
the form. 
 
Other aspects to consider, such as voluntary participation in the clinical study will be followed 
according to FDA guidance, IRB Guide for Researchers and Sponsor standard operating 
procedure.   
 
 


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Figure 1 Informed consent timelines. 
 
 
 
After Informed consent has been obtained, each participant should complete the following visits.  
 
• Visit 1 – Screening, during this period, the principal investigator will make the decision 
to determine whether the screened participant is eligible and whether the next visit can be 
scheduled. Once the principal investigator has evaluated the eligibility of the subject 
screened (up to 28 days), a randomization process will be conducted to assign the eligible 
subject either HB-adMSCs or Placebo. Randomization will only apply to eligible 
subjects. If a study participant does not meet the inclusion criteria during the screening 
process, he/she will be considered Screen Failure (SF) and does not need to be 
randomized to any group.  
 
• Visit 2 – Infusion 1, (Baseline): this visit will be used as a starting point for comparison 
of participant’s data. During this visit, eligible study participants will receive his/her first 
investigational product administration or placebo with a rigorous monitoring of vital 
signs for a total of 2 hours after drug exposure. Other study evaluations will be completed 
as part of this visit.  
 
• Visit 3 – Infusion 2: approximately 4 weeks after the initial investigational product 
administration this visit should be completed. Other study evaluations will be completed 
as part of this visit.  
 
• Visit 4 – Infusion 3: approximately 8 weeks after the initial investigational product 
administration this visit should be completed. Other study evaluations will be completed 
as part of this visit.  
 
• Visit 5 – Infusion 4: approximately 16 weeks after the initial investigational product 
administration this visit should be completed. Other study evaluations will be completed 
as part of this visit.  
 


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• Visit 6 – Infusion 5: approximately 24 weeks after the initial investigational product 
administration this visit should be completed. Other study evaluations will be completed 
as part of this visit.  
 
• Visit 7 – Infusion 6: approximately 32 weeks after the initial investigational product 
administration this visit should be completed. Other study evaluations will be completed 
as part of this visit.  
 
• Visit 8 – Safety Follow Up: approximately 42 weeks after the initial investigational 
product administration, active study participants will complete a follow up visit at the 
clinic site.    
 
• Visit 9 – End of Study, during this final visit (approximately 52 weeks after Week 0) a 
complete group of study assessments will be performed to evaluate the safety and 
efficacy of HB-adMSCs or Placebo administrations.  
 
Clinical assessments of disease activity will take place during the following visits:  
 
• Visit 1 – Screening  
• Visit 2 – Infusion 1 (Baseline)  
• Visit 4 – Infusion 3  
• Visit 6 – Infusion 5 
• Visit 8 – Follow Up  
• Visit 9 – End of Study  
 
Blood samples for safety assessments will be collected in as follows:  
 
• Visit 1 – Screening: after informed consent has been obtained, blood samples should be 
collected from a vein of the study’s participant arm, these lab results will help assess the 
subject's eligibility.   
 
• Visit 2 – Infusion 1, (Baseline): safety laboratory samples will be collected from the 
study participant's vein to establish a baseline for comparison with the laboratory results 
obtained in subsequent visits.  
 
• Visit 6 – Infusion 5: safety laboratory samples should be collected from a vein of the 
study’s participant arm during this visit.  
 
Visit 9 – End of Study: safety laboratory samples should be collected from a vein of the study’s 
participant arm during this visit. 


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For study participants who do not complete the study trial, a safety follow-up visit will be 
scheduled as follows:  
 
• For subjects who did not receive any of the investigational products and were eligible to 
participate in the trial, they will be invited to a safety follow-up visit, or Early termination 
visit (ETV) within 30 days after the last visit.  
 
• For subjects who received at least one dose of the investigational product, they will be 
invited to a safety follow-up visit, approximately 30 days following that single treatment.  
 
• For subjects who received more than one dose of the investigational product, they will be 
invited to a safety follow-up visit, approximately 30 days following the last treatment.  
 
 
Withdrawal Criteria  
 
In different situations, a study subject may withdraw from the study before the planned 
completion of the visits. One of these situations is mentioned below,  
 
1. Voluntary withdrawal: subject doesn’t want to continue receiving the investigational 
product.   
 
The principal investigator and designated staff must record the reason for the subject's 
withdrawal on the case report forms, specifically in the Early Termination Visit and /or a Note to 
File Form.  
 
Study participants discontinued from the clinical trial who received at least one infusion (HB-
adMSCs or placebo) will be invited to a Safety Follow-up visit approximately 30 days after that 
single infusion.  
 
Any withdrawal must be documented in the source documents and electronic case report forms. 
If the reason for the discontinuation is an adverse event or serious adverse event, the event must 
be followed until resolution by the principal investigator.  
 
The Sponsor may temporarily or permanently discontinue the clinical trial at any time for safety, 
ethical, compliance or other reasons. Study’s principal investigator and regulatory authorities 
will be notified about this decision and the reason of it.  
 
 
 
 


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Selection of Clinical Trial Population  
 
Clinical Trial Population   
 
This clinical trial is designed to include adult male and female outpatients with Relapsing 
Remitting Multiple Sclerosis. Study participants who fulfil all the inclusion criteria and none of 
the exclusion criteria are eligible for participation in the clinical trial. See below eligibility 
criteria: 
 
 Eligibility Criteria  
 
 
 Inclusion Criteria  
 
A study participant will be eligible for inclusion in this study only if all the following criteria 
apply:  
 
1. 
Male and female participants 18 – 75 years of age.  
2. 
Study participants must have been diagnosed with Relapsing Remitting Multiple 
Sclerosis (RRMS) for at least 6 months before study participation.  
3. 
Study participants must be stabilized on any MS therapy for at least 6 months prior to 
randomization.  
4. 
Study participants must agree not to increase or begin any Diseases Modifying Therapies 
for MS during participation in the clinical trial.   
5. 
Study participants must have an EDSS score between 3.0 to 6.5. (Patient must be able to 
walk).  
6. 
Study participants must have previously banked their mesenchymal stem cells with Hope 
Biosciences.  
7. 
Study participants should be able to read, understand and to provide written consent.  
8. 
Before any clinical-trial-related procedures are performed, informed consent must be 
obtained from the participants voluntarily. 
9. 
Female study participants should not be pregnant or plan to become pregnant during 
study participation and for 6 months after last investigational product administration. * 
10. 
Male participants, if their sexual partners can become pregnant, should use a method of 
contraception during study participation and for 6 months after the last administration of 
the investigated product. * 
11. 
Study participant is able and willing to comply with the requirements of this clinical trial.  
12. 
Participants in the study should have evidence of disease, as shown by MRIs of the brain 
or spinal cord, with the most recent being within 1 year of the screening date, and no 
other signs of relapse. 


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Exclusion Criteria 
 
A study participant will not be eligible for inclusion in this clinical trial if any of the following 
criteria apply:  
 
1. 
Pregnancy, lactation. Women of childbearing age who are not pregnant but do not take 
effective contraceptive measures. * 
2. 
Study participants with other types of multiple sclerosis, such as progressive relapsing, 
primary or secondary progressive. 
3. 
Study participant has any active malignancy, including but not limited to evidence of 
cutaneous basal, squamous cell carcinoma, or melanoma.  
4. 
Study participant has known addiction or dependency or has current substance use or abuse.  
5. 
Study participant has 1 or more significant concurrent medical conditions (verified by 
medical records), including the following:  
• Poorly controlled diabetes mellitus (PCDM) defined as history of deficient 
standard of care treatment and/or pre-prandial glucose >130mg/dl during 
screening visit or post-prandial glucose >200mg/dl.  
• Medical History of Chronic kidney disease (CKD) diagnosis and/or screening 
results of eGFR < 59mL/min/1.73m2.   
• Presence of New York Heart Association (NYHA) Class III/IV heart failure 
during screening visit.  
• Any medical history of myocardial infarction in any of the different types, such as 
ST-elevation myocardial infarction (STEMI) or non-ST-elevated myocardial 
infarction (NSTEMI), coronary spasm, or unstable angina.  
• Medical history of uncontrolled high blood pressure defined as a deficient 
standard of care treatment and/or blood pressure > 180/120 mm/Hg during 
screening visit.  
• Medical history of diseases such as, inherited thrombophilias, cancer of the lung, 
brain, lymphatic, gynecologic system (ovary or uterus), or gastrointestinal tract 
(like pancreas or stomach).  
• Medical history of conditions, such as recent major general surgery, (within 12 
months before the Screening), lower extremity paralysis due to spinal cord injury, 
fracture of the pelvis, hips, or femur.  
6. 
Study participant has received any stem cell treatment within 12 months before first dose of 
investigational product other than stem cells produced by Hope Biosciences. 
7. 
The study participant has received any experimental drug within 12 months before the first 
dose of the investigational product.  (Except for COVID-19 vaccinations)  
8. 
Study participant has a laboratory abnormality during screening, including the following:  
• White blood cell count < 3000/mm3  
• Platelet count < 80,000mm3  


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• Absolute neutrophil count < 1500/mm3  
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 10 upper 
limit of normal (ULN) x 1.5  
9. 
Study participant has any other laboratory abnormality or medical condition which, in the 
opinion of the investigator, poses a safety risk or will prevent the subject from completing the 
study. 
10. 
The study participant has any concurrent neurologic disease, including hereditary conditions 
that the principal investigator considers could interfere with the study participation. Some of 
these neurologic diseases could be Charcot-Marie-Tooth (CMT) or Spinocerebellar Ataxia 
(SCA).  
11. 
Study participant has any ongoing infection, including TB, CMV, EBV, HSV, VZV, hepatitis 
virus, toxoplasmosis, HIV, or syphilis infections, as well as hepatitis B surface antigen 
positive, and or/ hepatitis C PCR positivity. 
12. 
Study participant is unlikely to complete the study or adhere to the study procedures.  
13. 
Study participant has a previously diagnosed psychiatric condition which in the opinion of 
the investigator may affect self-assessments. 
14. 
Study participant with any systemic infection requiring treatment with antibiotics, antivirals, 
or antifungals within 30 days prior to first dose of the investigational product.  
15. 
Male study participants who plan to donate sperm during the study or within 6 months after 
the last dose. Female patients who plan to donate eggs or undergo in vitro fertilization 
treatment during the study or within 6 months after the last dose.  
16. 
Study participants who are determined by the Investigator to be unsuitable for study 
enrollment for other reasons.   
17. 
Participants' life expectancy must not have been considerably limited by other comorbidities, 
a history of previous myelodysplasia, or hematologic illness. 
* Acceptable reversible and permanent methods of birth control include: 
 
1. True sexual abstinence (abstaining from sexual activity during the entire period of risk).   
2. Surgery (occlusion bilateral tubal ligation, vasectomized partner).  
3. Hormonal contraceptives associated with ovulation inhibition (oral, injectable, implantable 
patch, or intravaginal).  
4. Intrauterine device (IUD), or intrauterine hormone-releasing system (IUS). 
 
Recruitment of Study participants  
 
This clinical trial has been created to enroll 24 study participants diagnosed with Relapsing 
Remitting Multiple Sclerosis. A single site located in Sugar Land; Texas will be used for this 
clinical trial. Each study participant will undergo a Screening visit, prior to Infusion 1 (Baseline). 
Each study participant will receive a unique subject identification number which must be entered 
in the screening log. This screening number will be assigned sequentially in the order in which 


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the study participants are screened. The result of the screening visit should be recorded in the 
screening log by the study delegated staff. See figure below with Screening log.  
 
Study Treatment Description  
 
In this clinical investigation, eligible study subjects will be randomized to either HB-adMSCs or 
placebo. Randomization process will be conducted during screening process by a designated 
study randomizer. See below the description of the study treatment.  
 
HB-adMSCs Infusions  
 
Study subjects must have banked their mesenchymal stem cells with Hope Biosciences to 
participate in this clinical trial. Study subjects who are randomly assigned during the screening 
process to the HB-adMSCs group will receive their own mesenchymal stem cells in each 
infusion with a dose of 200 million cells.  
 
Study subjects, investigators and study staff will be blinded to the assigned treatment. To 
maintain the blinding of this investigation, amber plastic bags shall be used to cover treatment 
bags. Only subject identification number, patient initials, date of birth and the phrase: “Caution: 
New Drug Limited by Federal law to Investigational Use (required by 21 CFR 312.6) will be on 
the bag label, to ensure proper distribution. 
 
Placebo Infusions  
 
Study subjects who are randomly assigned during the screening process to the Placebo group will 
receive Saline Solution 0.9% in each infusion.   
 
Study subjects, investigators and study staff will be blinded to the assigned treatment. To 
maintain the blinding of this investigation, amber plastic bags shall be used to cover treatment 
bags. Only subject identification number, patient initials, date of birth and the phrase: “Caution: 
New Drug Limited by Federal law to Investigational Use (required by 21 CFR 312.6) will be on 
the bag label, to ensure proper distribution. 
 
Each study treatment will be provided by Hope Biosciences, LLC after all quality control essays 
have been performed and the results are within normal range. 
 


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Treatment Regimen   
 
Study subjects will receive the allocated treatment (HB-adMSCs or Placebo) through intravenous 
infusion only, with a treatment duration of 32 weeks, infusion rate 4-5ml/min and total volume 
of 250 ml Sodium chloride 0.9%. Each study participant will receive a total of 6 doses of HB-
adMSCs or Placebo with a dosing regimen of approximately 4 to 8 weeks between infusions.   
 
Study Treatment Storage, Preparation and Administration Instructions.  
 
Each syringe with the study treatment (HB-adMSCs or Placebo) is individually packaged in a 
Styrofoam cooler with a temperature strip and icepacks. The product should not be stored since it 
is meant for immediate preparation and infusion. In the event of unanticipated delays, the 
product should be kept in a refrigerator (2° to 8°C) for a time not to exceed 96 hours. Do not 
freeze. Do not use any syringe or other infusion supplies beyond the expiration date. 
 
The infusion should be prepared by a designated unblinded pharmacist using aseptic technique 
with the following procedures: (detailed instructions will be available in the Investigational 
Product Manual):  
 
1. Gather all equipment and materials you need including cooler with HB-adMSCs or 
placebo.  
2. Don non-sterile gloves and clean countertop where infusion is to be prepared using 
antibacterial wipes according to manufacturing instruction. 
3. Remove and discard gloves, clean hands with hand sanitizer and allow to dry. 
4. Don non-sterile gloves. 
5. Open cooler and remove bag containing syringe with the study treatment.  
6. Check the randomization procedure by checking the study subject's identification number 
and date of birth.  
7. Visually confirm temperature tape is in biohazard bag and is within range (2° - 8° C), 
document compliance. 
8. Visually confirm syringe is closed with cap. 
9. Remove syringe from bag and begin mixing syringe, gently rocking back and as well as 
rolling between hands, bringing the study treatment to room temp, and suspending them 
into a homogenous solution.  No particulates should be visible.   
10. Inject the contents into a 250cc bag of normal saline for injection 
11. Properly label the infusion bag with the subject ID, D.O.B, preparation date, time and 
expiration and cover it with an amber bag.  
 
Once, the study treatment has been mixed by the unblinded pharmacist following the above 
procedures, the infusion nurse or designated study staff will administer the study treatment as 
follows:  


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1. 
Confirm that the subject number and DOB placed on the amber bag label belong to the 
subject receiving the infusion.  
2. 
Administer the infusion solution over a period of 1h (infusion rate 4-5ml/min).  
3. 
Do not store or reuse any unused portion of the infusion solution. Any unused product or 
waste material should be disposed in a biohazard container.  
4. 
Complete the source documents of the visit to accurately collect the start and end times of 
the infusion and add comments if necessary.  
5. 
The study’s subject will be monitored for a total of 2 hours from drug exposure to 
discharge. 
 
- During the Investigational product administration (1 hour) vital signs will be measured at 
minute 0, 15, 30, 45, and 60. 
 
- Post infusion, vital signs will be measured at minute 90 and 120.  
 
6. 
Follow study procedures as described in the schedule of assessments of the visit.  
 
Investigational Product Assignment (Randomization and Blinding) 
 
A total of 24 eligible subjects will be randomized to either placebo (approx. 12) or active drug 
(approx.12) (HB-adMSCs) in a 1:1 balanced design. The randomization will be applicable only 
to eligible subjects. If a subject is not eligible during the screening process for study 
participation, this subject shall not me randomized to any group.  
 
Randomization will be conducted using the REDCap randomization module. REDCap does not 
use an algorithm to dynamically randomize subjects, but rather a pre-determined, stratified, and 
permutated randomization schedule. The module allows for creating a custom allocation list, 
which serves as a lookup table for deciding how to randomize subjects. The allocation table is 
stratified to achieve even study treatment distribution within the following subgroups. Raw 
coded values corresponding to the table are in parenthesis following their representative 
category. 
 
• Multiple’s sclerosis severity (Mild vs Moderate):  
 
o Mild disability (1) (EDSS < 4) 
o Moderate disability (2) (EDSS > 4 and < 6.5)  
 
• Age:    < 55 (1) vs > 55 (2) 
• Gender: Female (1) or Male (2)  
 


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1:1 Drug to Control Group Distribution Rule 
 
The allocation table is structured so that there is 1 to 1 respective distribution between drug and 
control groups.  
 
Modifications to Allocation  
 
There are more permutations assignments created in the allocation table, than the 24 required to 
accommodate multiple subgroups and support possible drop-out scenarios. Once the 
randomization model is defined in REDCap, the allocation table will become locked and 
unmodifiable. If more allocations are necessary, REDCap has the capability to ONLY append to 
the existing allocation table and not replace it. 
 
Controlling Blinded Information 
 
REDCap system’s user privileges can be used to allow only certain users to be able to set up the 
randomization, perform the randomization, or view the allocation information. All REDCap end 
users will be blinded and will not have access to the randomization information with exception to 
the unblinded pharmacist and the personnel who will be responsible in setting up the 
randomization schedule and performing the randomization.  
 
Blinding for Dose Administration 
 
All subjects, investigators, and site staff will be blinded to treatment assigned. 
 
Amber plastic bags shall be used to cover sodium chloride (saline) bags with the product under 
investigation for infusion. Only subject identification number and date of birth will be on the bag 
label, to ensure proper distribution.  
 
For the preparation of the investigational product, Unblinded pharmacist (UP) will inject the 
investigational product into a 250 ml sodium chloride (Saline) infusion bag, cover it with an 
amber plastic bag and apply the label before delivering it to study site.  
 
Unblinded pharmacist, also identified as Mixer, will keep records of the treatment assigned to 
each subject in the unblinded pharmacy binder. Access to this pharmacist binder will be limited 
to the unblinded pharmacist.  
 
Blinding for Clinical Evaluators 
 
To minimize assessment bias, clinical evaluators (data analysts and physicians) will be trained on 
how to maintain blinding to treatment as best as possible. “Best as possible” means that blinding 


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will be maintained unless an adverse event or serious adverse events occurs that requires 
unblinding the physician, which is determined by the medical monitor or DSMB.  
 
Training includes review of the process of blinding, describing who will be responsible for 
assigning product for the appropriate group, labels that will be used to identify subjects but not 
treatment group, and the process that should be followed if an adverse event occurs, triggering 
review by medical monitor and/or DSMB. 
 
Prior and Concomitant Medications         
 
Concurrent and prior medications (up to one week before the screening visit) should be recorded 
in the subject’s medical history at the screening visit. This list of concomitant medications may 
be updated, if necessary, at the following visits.  
 
It is important to ask the subject about the start and end date of the current and prior medications, 
if the subject does not remember the specific date or month, it is recommended to include the 
approximate year to give an estimate of how long the patient has been taking the medication. 
 
Trial Procedures    
 
The trial includes an up to 28 days screening period, a 32-week Treatment Period and a 20-week 
Safety Follow-up Period. All periods are associated with evaluations and procedure that must be 
performed at specific time points as represented in Table 4 Schedule of Assessments.  
 
 
 
 
 


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Trial Schedule of Assessments.  
 
Table 4 Schedule of Assessments.  
 
 
Visit 1 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit Names 
Screening 
INF 1 
INF 2 
INF 3 
INF 4 
INF 5 
INF 6 
Follow 
Up 
EOS 
Window Period 
Up to 28 
days 
+ 7 
days 
+ 7 
days 
+ 7 
days 
+ 7 
days 
+ 7 
days 
+ 7 
days 
+ 7 
days 
+ 7 
days 
Visit Weeks 
N/A 
0 
4 
8 
16 
24 
32 
42 
52 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Laboratory Samples 1 
X 
X 
 
 
 
X 
 
 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded Disability 
Status Scale (EDSS) 
X 
 
 
 
 
 
 
 
X 
The Barthel Index  
 
X 
 
X 
 
X 
 
X 
X 
9-Hole Peg Test 
 
X 
 
X 
 
X 
 
X 
X 
Multiple Sclerosis Quality 
of Life Inventory 54 
 
X 
 
X 
 
X 
 
X 
X 
Patient Health 
Questionnaire 9 (PHQ-9)  
 
X 
 
 
 
 
 
 
X 
Study Treatments 
Administration 
 
X 
X 
X 
X 
X 
X 
 
 
24 hours Telephone 
Encounter 
 
X 
X 
X 
X 
X 
X 
 
 
Video Documentation 
 
X 
 
 
 
X 
 
 
X 
AE and SAE assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
1 Collection of laboratory samples (CBC, CMP & Coagulation Panel) 
 
Randomization 


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Study Visits 1 to 9.           
 
Visit 1 – Screening.  
 
At the Screening Visit (Visit 1), study participants’ information will be collected by study’s 
delegated personnel for evaluation of trial eligibility. The following information is required to 
determine eligibility:   
 
1. 
Signing Informed Consent Form (prior to any trial-related activities).  
2. 
Collection of demographic information, such as age, race, ethnicity, date of birth, gender, 
and relevant medical and surgical history.  
3. 
Collection of Medical History and concomitant medications, including relevant 
information about the past and present health of study participants.  
4. 
Inclusion and Exclusion criteria evaluation.  
5. 
Measurement of vital signs including respiratory rate, body temperature, blood pressure, 
pulse rate, oxygen saturation, and measurement of weight and height.   
6. 
Collection of laboratory samples, including Comprehensive Metabolic Panel (CMP), 
Complete Blood Count (CBC), Coagulation Panel, and Urine pregnancy test if female of 
childbearing potential. 
7. 
Physical examination by Principal Investigator, including clinical assessments such as 
Expanded Disability Status Scale (EDSS).   
 
Within 28 days of the Visit 1 - Screening, the principal investigator must decide participant’s 
eligibility. Once, the eligibility of the subject has been confirmed by the principal investigator, 
the randomization process will be conducted.  
 
Visit 2 and 6 – Infusion 1 (Baseline) and Infusion 5 
 
The following procedures are required during this visit:  
 
1. 
Update medical history and concomitant medications if any change occurred since last 
visit.  
2. 
Measure vital signs including respiratory rate, body temperature, blood pressure, pulse 
rate, oxygen saturation and measurement of weight.  
3. 
Collect laboratory samples, including Comprehensive Metabolic Panel (CMP), Complete 
Blood Count (CBC), Coagulation Panel and Urine pregnancy test if female of 
childbearing potential. 
4. 
Physical examination by Principal Investigator, including clinical assessments such as 
The Barthel Index, 9 Hole Peg Test, Multiple Sclerosis Quality of Life (MSQOL)-54 
Instrument and Patient Health Questionnaire (PHQ-9 is only needed during Infusion 1 
and EOS).    


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5. 
Investigational product administration by delegated study personnel. HB-adMSCs or 
Placebo should only be administered intravenously, with a dosing rate of 4-5ml/min and a 
vital sign monitoring of two hours post-drug exposure. Monitoring time may be 
prolonged if decided by principal investigator. Vital signs must be monitored as follows:  
6. 
A video documenting study participant walking and standing from sitting will be 
recorded during this visit.  
7. 
Assess the incidence of any adverse event.  
8. 
24 hours after administration of the investigational product, study participants will be 
contacted by telephone call to assess the incidence of adverse events.   
 
 Visit 3, 5 and 7 – Infusions 2, 4 and 6.  
 
1. 
Update medical history and concomitant medications if any change occurred since last 
visit.  
2. 
Measure vital signs including respiratory rate, body temperature, blood pressure, pulse 
rate, oxygen saturation and measurement of weight. 
3. 
Physical examination by Principal Investigator.   
4. 
Investigational product administration by delegated study personnel: HB-adMSCs or 
Placebo should only be administered intravenously with a dosing rate of 4-5ml/min and 
vital sign monitoring of two hours post-drug exposure. Monitoring time may be 
prolonged if decided by principal investigator. The monitoring of vital signs shall be the 
same as represented in Figure 8.  
5. 
Assess the incidence of any adverse event.  
6. 
24 hours after administration of the investigational product, study participants will be 
contacted by telephone call to assess the incidence of adverse events. 
 
   
 Visit 4 – Infusion 3 
 
1. 
Update medical history and concomitant medications if any change occurred since last 
visit.  
2. 
Measure vital signs including respiratory rate, body temperature, blood pressure, pulse 
rate, oxygen saturation and measurement of weight. 
3. 
Physical examination by Principal Investigator, including clinical assessments such as 
The Barthel Index, 9 Hole Peg Test and, Multiple Sclerosis Quality of Life (MSQOL)-54 
Instrument.  
4. 
Investigational product administration by delegated study personnel: HB-adMSCs or 
Placebo should only be administered intravenously, with a dosing rate of 4-5ml/min and 
vital sign monitoring of two hours post-drug exposure. Monitoring time may be 


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prolonged if decided by principal investigator. The monitoring of vital signs shall be the 
same as represented in Figure 8.  
5. 
Assess the incidence of any adverse event.  
6. 
24 hours after administration of the investigational product, study participants will be 
contacted by telephone call to assess the incidence of adverse events.   
 
 
Visit 8 – Safety Follow Up 
 
1. 
Update medical history and concomitant medications if any change occurred since last 
visit.  
2. 
Measure vital signs including respiratory rate, body temperature, blood pressure, pulse 
rate, oxygen saturation and measurement of weight. 
3. 
Physical examination by Principal Investigator, including clinical assessments such as 
The Barthel Index, 9 Hole Peg Test and, Multiple Sclerosis Quality of Life (MSQOL)-54 
Instrument. 
4. 
Assess the incidence of any adverse event since last visit.  
 
 
Visit 9 – End of Study 
 
1. 
Update medical history and concomitant medications if any change occurred since last 
visit.  
2. 
Measure vital signs including respiratory rate, body temperature, blood pressure, pulse 
rate, oxygen saturation and measurement of weight. 
3. 
Physical examination by Principal Investigator, including clinical assessments such as 
Expanded Disability Status Scale (EDSS), The Barthel Index, 9 Hole Peg Test, Multiple 
Sclerosis Quality of Life (MSQOL)-54 Instrument and Patient Health Questionnaire 
(PHQ-9 is only needed during Infusion 1 and EOS).       
4. 
Collection of laboratory samples, including Comprehensive Metabolic Panel (CMP), 
Complete Blood Count (CBC), Coagulation Panel and Urine pregnancy test if female of 
childbearing potential. 
5. 
A video documenting study participant walking and standing from sitting will be 
recorded during this visit.  
6. 
Assess the incidence of any adverse event since last visit.  
 
 
Unscheduled Visits  
 


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The Investigator may at his/her discretion arrange for a study participant to have an unscheduled 
visit (UNS). Some of the circumstances by which a study participant will be called for a UNS 
visit are:   
 
• Adverse events (AEs) that require follow-up.  
• Collection of laboratory samples for safety reasons.  
• Procedures missed at previous study visits.  
 
 All unscheduled visits should be documented in the study’s participant source. 
 
 
Trial Assessments  
 
Assessments Related to Endpoints  
 
 
Expanded Disability Status Scale (EDSS) 
 
The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple 
sclerosis and monitoring changes in the level of disability over time. It is widely used in clinical 
trials and in the assessment of patients with MS. 
 
The scale was developed by a neurologist called John Kurtzke in 1983 as an advance from his 
previous 10 step Disability Status Scale (DSS). 
 
The EDSS scale ranges from 0 to 10 in 0.5-unit increments that represent higher levels of 
disability. Scoring is based on an examination by a neurologist. 
 
EDSS steps 1.0 to 4.5 refer to people with MS who can walk without any aid and is based on 
measures of impairment in eight functional systems (FS): 
 
• pyramidal – muscle weakness or difficulty moving limbs 
• cerebellar – ataxia, loss of balance, coordination, or tremor 
• brainstem – problems with speech, swallowing and nystagmus 
• sensory – numbness or loss of sensations 
• bowel and bladder function 
• visual function - problems with sight 
• cerebral functions - problems with thinking and memory 
• other 
 


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A functional system (FS) represents a network of neurons in the brain with responsibility for 
tasks. Each FS is scored on a scale of 0 (no disability) to 5 or 6 (more severe disability).  
 
EDSS steps 5.0 to 9.5 are defined by the impairment to walking. The scale is sometimes 
criticized for its reliance on walking as the main measure of disability. 
 
Although the scale takes account of the disability associated with advanced MS, most people will 
never reach these scores. A large study that looked at people with MS at a clinic in Ontario (prior 
to the development of the expanded version) found that 51% of people had a DSS score of 5 or 
lower. 88% had a score of 7 or lower (Multiple Sclerosis Trust, 2020). 
 
Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument.  
 
The MSQOL-54 is a comprehensive health-related quality of life measure incorporating general 
and MS-specific questions into a single instrument. The developers used the SF-36 as a base and 
added 18 questions to address MS-specific problems, including fatigue and cognitive function. 
This 54-item questionnaire provides 12 subscales, two summary scores, and two extra single-
item measures. The subscales are physical function, role limits-physical, emotional role 
restrictions, pain, emotional well-being, energy, health perceptions, social position, cognitive 
function, health distress, overall quality of life, and sexual function (National Multiple Sclerosis 
Society, 2021).  
 
The Barthel Index  
 
When it comes to patients with chronic, debilitating illnesses, the Barthel index is an ordinal 
scale that evaluates functional independence in the domains of personal care and mobility. A 
total of ten variables describing activities of daily living and mobility are considered, with a 
higher number reflecting better capacity to operate independently. The Barthel Index assesses the 
level of help needed by a person on a set of ten activities of daily living (ADL) related to 
mobility and self-care (Elite Learning, 2008). 
 
9-Hole Peg test  
 
The 9-HPT is a short, standardized upper extremity exam. In MS research, gait analysis has been 
given precedence over arm and hand function analysis. In recent years, clinical investigations 
have increasingly recognized the value of assessing arm and hand function, particularly in 
severely disabled patients. The 9-HPT has recently become one of the most widely utilized upper 
extremity measurements in MS. Many qualified examiners can administer the 9-HPT since it is 
short and standardized. (National Multiple Sclerosis Society, 2021).  
 
PHQ-9 (Patient Health Questionnaire-9) 
 
Suicide prevention programs may also have a clinical component, which refers to how 
individuals are evaluated and treated for mental health problems or suicidal thoughts in medical 
facilities. The PHQ-9 is the most used depression and suicidal thoughts screening test. Other 


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screening methods exist, although some are tailored to certain populations or situations. The 
Patient Health Questionnaire (PHQ) is a self-administered version of the PRIME-MD diagnostic 
tool for common mental illnesses (Kroenke, 2001). 
 
 
Physical Examinations  
 
A complete physical examination will be performed by the principal investigator or delegated 
sub-investigator, including general appearance, head, eyes, ear, nose, and throat (HEENT), neck, 
cardiovascular, thorax/lungs, abdomen, genitourinary, musculoskeletal, lymph nodes, skin, 
neurological and mental status examination, height (at Screening only), and body weight at 
Visits 1, 2, 3, 4, 5, 6, 7, 8 and 9.  
 
The principal investigator or delegated sub-investigator will evaluate the clinical significance of 
abnormal findings identified during physical examinations. Pre-existing conditions diagnosed 
through assessments and examinations at the screening visit or during the screening period are 
not adverse events but are recorded as medical history. If any clinically significant abnormal 
findings are discovered after informed consent or any pre-existing conditions worsen during the 
trial, these must be recorded as adverse events. 
 
Vital Signs   
 
Vital signs will be measured at Visits 1, 2, 3, 4, 5, 6, 7, 8 and 9 and will include respiratory rate, 
pulse rate, blood pressure (measured after the study participant has been in a seated position for 
more than 5 minutes of rest), body temperature and oxygen saturation. Clinical significance of 
any abnormal result must be evaluated by principal investigator. Clinically significant abnormal 
findings will be reported as adverse events.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Safety Laboratory Parameters   
 
The following laboratory parameters should be collected at Visit 1, 2, 6 and 9.   
 
• Comprehensive Metabolic Panel, also known as CMP or Chemistry Panel is a group of 
different tests that measure several substances in the study’s participant blood. The 
following tests are included in this panel:  
 
 


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• Complete Blood Count, also known as CBC, hemogram or CBC with Differential is a 
group of tests that evaluate the cells that circulate in blood, including red blood cells 
(RBCs), white blood cells (WBCs), and platelets.  
 
• Coagulation Tests including Prothrombin Time (PT or PT-INR) to identify any 
coagulation disorder during study participation.  
• Urine Pregnancy Test, a urine sample, preferably collected during morning time, to 
confirm pregnancy during study participation. This test will be limited to Women of 
Childbearing Potential (WOCBP).  
Other Assessments   
 


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Demography    
 
Demographic data will be collected at the Screening Visit, including age, race, ethnicity, date of 
birth and gender.  
 
Medical and Surgical History    
 
Medical information on any previous concomitant illnesses, other than Multiple Sclerosis should 
be collected during Screening Visit and updated if needed during the following study visits. For 
planned procedures/hospitalizations during the clinical trial, documentation should be completed 
at the time of the Screening. 
 
Multiple Sclerosis and Previous Therapy for this disease    
 
The date of diagnosis of Multiple Sclerosis, as well as previous treatments, will be recorded 
during Screening visit.  
 
Concomitant Medication Review     
 
Data concerning concomitant medications and procedures will be collected throughout the 
clinical trial. This data will be obtained at scheduled or unscheduled visits based on information 
provided by the patient.  
 
Handling of Biological Samples  
 
Sampling tubes, material for shipments of the samples and a laboratory manual detailing all 
sample collection and shipment procedures will be provided and distributed to the clinical trial 
site by the selected laboratory. Laboratory samples will be collected as per protocol during Visit 
1 – Screening, and/or Visit 2 – Infusion 1 (Baseline), Visit 6 - Infusion 5 and Visit 9 – End of 
Study.  
 
 
Adverse Events   
 
Definitions 
 
Unanticipated Problems Involving Risk to Subjects or Others 
 
Any incident, experience, or outcome that meets all the following criteria:  
 


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• Unexpected in nature, severity, or frequency (i.e., not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators brochure, 
etc.) 
 
• Related or possibly related to participation in the research (i.e., possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research.  
 
• Serious (as defined below) “Serious” is different than “severe” as reported in the CTC 
criteria that applies a grade to the AE. 
 
Adverse Event 
 
An adverse event (AE) is any symptom, sign, illness, or experience that develops or worsens in 
severity during the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are adverse events if the abnormality: 
 
• results in study withdrawal 
• 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 
 
Serious Adverse Event 
 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening but are clearly 
of major clinical significance. 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.  
 


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All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, the study treatment follow-up is defined as approximately 20 weeks following the last 
administration of study treatment.  
 
Recording of Adverse Events  
 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source documents and CRF and in the appropriate adverse 
event section of the source documents.  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document and CRF, though 
should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the outcome.  Any serious 
adverse event that occurs after the study period and is possibly related to the study treatment or 
study participation should be recorded and reported immediately. 
 
Reporting of Serious Adverse Events and Unanticipated Problems.  
 
Investigator and the Sponsor must follow reporting timelines if any Serious Adverse Event of 
Unanticipated Problem occurs to the subject. Also, if any of them have the following criteria, it 
must be reported in a timely manner:  
 
• related to study participation 
• unexpected  
• serious or involve risks to subjects or others  
 
This report should include the minimum necessay information provided in the following table:  
 
Stopping Rules   
 


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Infusion Stopping Rules  
 
Study treatment infusion will be stopped if a least one of the following events occur:  
 
1. 
Allergic reaction as evidenced by severe dyspnea (defined as intense tightening of chest, 
air hunger, breathlessness or feeling of suffocation), bronchospasm (defined as coughing, 
wheezing, difficulty breathing) or hypoxia (defined as pulse oximeter reading of less than 
90%) after the product has been administered intravenously.  
 
2. 
Patient verbally decline the treatment at any moment prior, or during the infusion.   
 
3. 
Hyperpyrexia develops after infusion administration begins (core body temperature 
greater than or equal to 104°F).  
 
4. 
Principal Investigator may stop the infusion at any time, based upon PI’s discretion. 
   
5. 
Malignant Hypertension (180/120 mm/Hg) 
 
6. 
Sudden Severe Hypotension (30-40 mm/Hg drop from pre-infusion level) 
 
If an infusion is stopped for a subject due to an adverse event or serious adverse event, including 
but not limited to hypersensitivity reaction/anaphylaxis, no additional study treatment will be 
given to the study participant who develops the event. Although, the study participant will not 
receive the investigational product, he or she must be followed for safety purposes according to 
the protocol.  
 
Study Stopping Rules  
 
This Clinical Trial will stop if any of the following events are present:  
 
1. 
Subject’s Death.  
 
2. 
Occurrence of any thromboembolic event during or after HB-adMSCs administrations 
(up to 72 hours).  
 
3. 
Any cerebrovascular ischemia or seizure event occurring within 72 hours after any of the 
investigational product administrations.  
 
4. 
Any Serious Adverse Events determined to be related to the following:  
 


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- 
When there is one CTCAE.v5 grade 4 or 5 AE, irrespective of attribution. 
 
- 
Either any CTCAE Grade 2 adverse event that persists for more than two weeks, or 
any Grade 3 adverse event, that occurs within 72 hours after product administration. 
 
Should the study participant discontinue study treatment he/she will be followed for safety 
according to the protocol safety monitoring plan. The study participant will receive follow up 
communication via phone calls and/or electronically to ascertain the outcome until resolved 
fully. All will be documented as per protocol. 
 
All changes to the study stopping rules shall be reviewed by FDA.  If the study is suspended for 
any reason, it will not be re-opened until FDA agrees.  Regardless of whether the study is 
stopped or suspended all subjects will be followed to the EOS as per protocol. 
 
Statistical Methods    
 
Sample size consists of up to 24 subjects who have been diagnosed with Relapsing Remitting 
Multiple Sclerosis. All data collected from subjects who are enrolled and received the 
investigational product will be analyzed. The incidence of Adverse Events and Serious Adverse 
Events will be recorded and reported. Efficacy will be measured by improvement of subject’s 
signs and symptoms associated with Multiple Sclerosis. Interim analysis of all safety and 
efficacy data may be performed at any time deemed appropriate by the Sponsor. Although, the 
subject’s data may be analyzed at any time, a data analysis of all available data will be conducted 
when a least 10 subjects in each group have completed Week 24. Data may be analyzed for 
internal informational purposes, reports, presentations, and manuscripts.   
 
A repeat measure mixed model will be used to assess within-subject changes from baseline. 
correction for multiple comparisons will be employed for post-hoc comparisons. Multiple 
Sclerosis’s assessment scores (i.e., MSQOL) at screening and infusion 1 (before treatment) will 
be averaged and treated as a baseline. Averaging is performed to minimize sources of variance 
(i.e., patient condition, assessors) and particularly to establish a reliable baseline from which to 
establish changes.  
 
 
Data Handling     
 
Case Report Forms (CRF) 
 
 


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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. Reports received by the site, or 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 if applicable.  
 
The completion, review, and approval of all CRFs, as well as the completeness and authenticity 
of all clinical and laboratory data entered on these CRFs, are always the PI’s personal 
responsibility. Signature of Principal Investigator will be required to attest that the information 
contained on the CRFs is accurate.  
 
Original CRFs should not be made available in any form to third parties, except for authorized 
representatives of Hope Biosciences Stem Cell Research Foundation or appropriate regulatory 
authorities, without written permission from Hope Biosciences Stem Cell Research Foundation.     
 
Changes in the Conduct of the Clinical Trial       
 
Protocol Amendments  
 
Any change to the protocol will need to have a protocol amendment submitted to the IND, and 
FDA and IRB must agree prior to proceeding.  
 
Premature Clinical Trial Termination  
 
Both the Study Investigator and Sponsor have the right to terminate the clinical trial at any time.  
Should this become necessary, the procedures will be agreed upon after consultation between the 
two parties. In terminating the clinical trial, the Sponsor and the Study Investigator will ensure 
that adequate consideration is given to the protection of the best interests of the study 
participants. Regulatory authorities and IRB will be informed. 
 
In addition, the Sponsor reserves the right to terminate the participation of any clinical trial site. 
Conditions that may warrant termination include, but are not limited to:  
 
• Insufficient adherence to protocol requirements  
 
• Failure to enter patients at an acceptable rate 
 
Reporting and Publication        
 


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Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published, or passed on to any third party without the consent of the study sponsor.   
Any investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
Archiving           
 
Investigator File  
 
The study investigator is responsible for maintaining all the records (protocol and protocol 
amendments, completed source and case report documents, signed informed consent forms, 
relevant communications, and all other supporting documents) which allow to conduct the 
clinical trial at the site in compliance with ICH-GCP. The study site should retain such 
documents until at least 2 years after the last approval of a marketing application or at least 2 
years after the formal discontinuation of clinical development of the investigational product. 
These documents should be retained for a longer period if required by the applicable regulatory 
requirements in which the study is being conducted. Patient identification codes (patient names and 
corresponding study numbers) will be retained for this same period. The Investigator must contact 
Sponsor prior to disposing of any study records. 
 
Trial Master File  
 
The Sponsor will archive the Trial Master File in accordance with ICH-GCP and applicable 
regulatory requirements. 
 
 
 

SAP_001.pdf: 
 
 
 
Hope Biosciences Research Foundation 
HBMS01 
 
Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Page 1 of 24 
 
Department 
: Data management and Biostatistics 
Information Type 
: Statistical Analysis Plan (SAP) 
 
Title 
: A Randomized, Double-Blind, Single Center, Phase 2, 
Efficacy and Safety Study of Autologous HB-adMSCs vs 
Placebo for the Treatment of Patients with Multiple Sclerosis 
Product 
: HB-adMSCs 
– 
Hope 
Biosciences 
adipose 
derived 
mesenchymal stem cells 
Effective date 
: 20-Sep-2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Description: 
• The purpose of this SAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol HBPCOVID02.  
• This SAP is intended to describe the planned safety, efficacy and tolerability 
analyses required for the study. 
• This SAP is to convey the content of the complete statistical analysis 
deliverables. 
 
This confidential document is the property of Hope Biosciences Research Foundation. 
No unpublished information contained herein may be disclosed without prior written 
approval from Hope Biosciences Research Foundation. Access to this document must 
be restricted to relevant parties.


 
 
 
Hope Biosciences Research Foundation 
HBMS01 
 
Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Page 2 of 24 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol HBMS01. 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
 
2.1. 
Study Objective(s), Estimand(s) and Endpoint(s) 
 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
• To investigate the efficacy of 
intravenous 
infusions 
of 
HB-
adMSCs vs Placebo in patients with 
Multiple Sclerosis as determined by 
improvements in Multiple Sclerosis 
Quality 
of 
Life 
(MSQOL)-54 
Instrument. (Time frame: Baseline to 
Week 52). 
• Changes from Baseline at Weeks 52 in 
Multiple 
Sclerosis 
Quality 
of 
Life 
(MSQOL)-54 Instrument scores following 
treatment with HB- adMSCs or Placebo.  
This 54-item questionnaire provides 12 
subscales, two summary scores, and two 
extra single-item measures. The subscales 
are physical function, role limits-physical, 
emotional role restrictions, pain, emotional 
well-being, energy, health perceptions, 
social function, cognitive function, health 
distress, overall quality of life, and sexual 
function. 
Secondary Objective 
Secondary Endpoint 
• To evaluate the efficacy of intravenous 
infusions of HB-adMSCs vs. Placebo in 
patients with Multiple Sclerosis as 
determined by changes in Expanded 
Disability Status Scale (EDSS) (Time 
frame: Baseline to Week 52). 
• To assess the efficacy of intravenous 
infusions of HB-adMSCs vs. Placebo in 
patients with Multiple Sclerosis as 
determined by changes in The Barthel 
Index (Time frame: Baseline to Week 
52). 
• To determine the efficacy of intravenous 
infusions of HB-adMSCs vs. Placebo in 
patients with Multiple Sclerosis as 
determined by changes in 9-Hole Peg 
Test (Time frame: Baseline to Week 52). 
• Change from baseline at Week 52 in Total 
Expanded Disability Status Scale (EDSS) 
scores following treatment with HB- 
adMSCs or Placebo 
 
• Change from baseline at Week 52 in 
Barthel Index scores following treatment 
with HB- adMSCs or Placebo 
 
 
• Change from baseline at Week 52 in 9-
Hole Peg Test scores following treatment 
with HB- adMSCs or Placebo 
 


 
 
 
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Objectives 
Endpoints 
• To identify the safety of intravenous 
infusions of HB-adMSCs vs. Placebo in 
patients with Multiple Sclerosis as 
determined by changes in Patient Health 
Questionnaire (PHQ-9) (Time frame: 
Baseline to Week 52). 
• To assess the safety of intravenous 
infusions of HB-adMSCs vs. Placebo in 
patients with Multiple Sclerosis as 
determined by the incidence of adverse 
events or serious adverse events (Time 
frame: Baseline to Week 52). 
 
 
• Change from baseline at Week 52 in 
Patient Health Questionnaire (PHQ-9) 
scores following treatment with HB-
adMSCs or Placebo 
 
• Incidence of treatment-emergent Adverse 
Event (TEAEs) and serious Adverse 
Events (SAEs) 
• Incidence and risk of AEs of special 
interest (serious or nonserious), including 
thromboembolic events, peripheral events 
defined as, thromboembolism of the 
extremities, 
also 
infections 
and 
hypersensitivities. 
• Clinically 
significant 
changes 
in 
laboratory values, vital signs, weight, 
physical examination results and Multiple 
Sclerosis concomitant medications. 
 


 
 
 
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2.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
This study will be a randomized, double-blind, single center, phase 
2 study to assess efficacy and safety of multiple HB-adMSCs vs. 
Placebo for the treatment of Multiple Sclerosis. The trial includes,  
• A screening period of up to 4 weeks 
• A 32-week treatment period while on randomized study 
treatment 
§ Infusion 1 (Week 0), Infusion 2 (Week 4), Infusion 3 
(Week 8), Infusion 4 (Week 16), Infusion 5 (Week 24) 
and Infusion 6 (Week 32) 
• A safety Follow-up period of 20 weeks after the last 
investigational product administration. 
§ Follow up at week 42 and end of study at Week 52 
• 24 Subjects 
• 2 Treatment groups 
§ Group 1 → HB-adMSCs 
§ Group 2 → Placebo 
Study 
Intervention 
• Active Product: HB- adMSCs (Hope Biosciences adipose 
derived mesenchymal stem cells) 
§ Dose: 200 million 
§ Route: Intravenous 
§ Regimen: Weeks 0, 4, 8, 16, 24 and 32. 
• Placebo: Saline Solution 0.9% 
§ Dose: N/A 
§ Route: Intravenous 
§ Regimen: Weeks 0, 4, 8, 16, 24 and 32. 
• Duration of administration 1 hour 
• Study treatment details, 


 
 
 
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Overview of Study Design and Key Features 
 
 
Study 
Intervention 
Assignment 
• Participants will be randomised 1:1 to receive HB-adMSCs 
active treatment or Placebo. 
Interim 
Analysis 
• No interim analysis will be performed in this study 
 
3. 
STATISTICAL HYPOTHESES 
The primary analysis will test whether HB-adMSCs is superior to Placebo according to 
the following statistical hypotheses: 
Null hypothesis H0: The difference in change from baseline at Weeks 52 in Multiple 
Sclerosis Quality of Life (MSQOL)-54 Instrument scores between treatment groups 
(HB-adMSCs – Placebo) is equal to zero. 
Alternative hypothesis H1: The difference in change from baseline at Weeks 52 in 
Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument scores between treatment 
groups (HB-adMSCs – Placebo) is not equal to zero. 
Secondary analysis will be tested for mean difference for change from Baseline to Week 
52 for efficacy endpoints for both treatment groups, 
Null hypothesis H0: D  = 0 
Alternative hypothesis H1: D ≠ 0 
 
 
 


 
 
 
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3.1. Multiplicity Adjustment 
The Bonferroni-Holm method for adjustment of multiplicity adjustment is performed 
for all secondary efficacy endpoint of interest.  
 
Bonferroni-Holm method starts with ordering the p-values in increasing order and starts 
with testing the hypothesis with the lowest p-value on the 5/k% level (two-sided), where 
k is the number of hypotheses in the procedure. If significant, the testing proceeds to 
comparing the next lowest p-value with 5/(k-1)%. 
 
4. 
ANALYSIS SETS 
Population 
Definition / Criteria 
Analyses 
Evaluated 
Safety 
analysis set 
• 
All randomised subjects who received at 
least one dose of HB-adMSCs infusion or 
placebo. 
• 
If participants receive a treatment different 
to their randomized treatment, they will be 
analysed according to the treatment actually 
received. 
• 
Safety 
• 
Study 
Population 
Efficacy 
analysis set 
• 
All randomized participants who received 
all 6 infusions of HB-adMSCs or placebo. 
• 
Participants will be analysed according to 
their randomized treatment. 
• 
Efficacy 
Screened 
Population 
• 
This population consists of all subjects who 
signed an ICF to participate in the clinical 
trial. 
• 
This 
population 
will 
be 
used 
for 
summarizing screening failures and reasons 
for screening failures. 
• 
Study 
Population 
 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed (or withdrawn from) the study as defined in the 
protocol. 
2. All required database cleaning activities have been completed and final database 
release and database lock has been declared by Data Management. 
 
5.1.1. 
General Methodology 
Unless otherwise stated, all hypotheses will be tested at a 2-sided significance level of 
0.05 and 95% confidence interval. All continuous measurements will be summarised 
descriptively at each visit by treatment using observed data. 


 
 
 
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Summary of continuous variables will be presented using N, Mean, 95% confidence 
interval of mean, Standard Error of mean (SE), Standard Deviation (SD), Median and 
Range (Minimum and Maximum). The categorical variables will be presented using 
number and percentage based on N. 
For measurements over time mean values will be plotted to explore the trajectory over 
time. Observed data will be used as the basis for plotting data along with bars as +/- SE, 
not otherwise specified. 
As a primary analysis, a standard Analysis of Covariance (ANCOVA) will be applied 
for primary and secondary endpoint to test the significance of the effects of the treatment 
at Week 52. The model includes treatment as fixed factor and the corresponding baseline 
value as a covariate. 
A parametric Repeated Measures Analysis (RMA) Model will be applied as a secondary 
analysis to test the significance of the effects of the treatment at Week 4, Week 8, Week 
16, Week 24, Week 32, Week 42 and Week 52 including baseline as covariate. 
Presentation of results from a statistical analysis model will include the estimated mean 
treatment effects (Least Square Means (LSMeans)). For all endpoints analysed 
statistically, estimated mean treatment differences will be presented together with two-
sided 95% confidence intervals and p-values, 
HB-adMSCs - Placebo 
 
Pairwise t-test will be performed on the efficacy endpoints to test the difference between 
baseline and week 52 (EOS) as secondary analysis. Data for all the efficacy outcomes 
will be checked for normality (Shapiro-Wilk Test). When there is a larger deviation of 
data distribution from normality, appropriate non-parametric test will be used. 
Additionally, RMA and ANCOVA in a Bayesian framework using a non-informative 
prior will be conducted to estimate the posterior distribution and to estimate the 
probablity that the true treatment difference of change from baseline to Week 4, Week 
8, Week 16, Week 24, Week 32, Week 42 and Week 52. 
Study population analyses including analyses of subject disposition, demographic and 
baseline characteristics, medical history, prior and concomitant medications. 
Disposition summary includes, subject screened, randomized and disposition at end of 
study – Week 52 along with reasons for withdrawals. Subjects in different analysis 
populations also will be presented. 
The screen failure table includes total number of screened subjects and reasons. The 
percentage in the screen failure table will be calculated based on total number of 
screened subjects as denominator. 
 
5.1.2. Baseline Definitions 
For all endpoints, the baseline value will be the latest pre-treatment assessment visit 
with a non-missing value. i.e., If an assessment has been made both at screening visit 
(Visit 1) and Week 0 infusion 1 visit (Visit 2, Week 0), the value from the Week 0 visit 
is used as the baseline value. If the value measured at the Week 0 visit is missing and 


 
 
 
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the assessment also has been made at screening, then the screening value is used as the 
baseline value. 
 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
 
Change from baseline calculated as: Post-baseline value – Baseline 
 
5.2. 
Primary Endpoint(s) Analyses 
The primary objective of this study is to compare HB- adMSCs to Placebo on Multiple 
Sclerosis Quality of Life (MSQOL)-54 Instrument scores. Efficacy analysis set will be 
used for this analysis. The details of the planned displays are in programming 
specification document. 
 
5.2.1. 
Definition of endpoint(s) 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
• To investigate the efficacy of 
intravenous 
infusions 
of 
HB-
adMSCs vs Placebo in patients with 
Multiple Sclerosis as determined by 
improvements in Multiple Sclerosis 
Quality 
of 
Life 
(MSQOL)-54 
Instrument. (Time frame: Baseline 
to Week 52). 
• Changes from Baseline at Weeks 52 in 
Multiple Sclerosis Quality of Life 
(MSQOL)-54 
Instrument 
scores 
following treatment with HB-adMSCs 
or Placebo.  
This 54-item questionnaire provides 12 
subscales, two summary scores, and two 
extra 
single-item 
measures. 
The 
subscales are physical function, role 
limits-physical, 
emotional 
role 
restrictions, pain, emotional well-being, 
energy, 
health 
perceptions, 
social 
function, cognitive function, health 
distress, overall quality of life, and 
sexual function. 
 
Data from the MSQOL-54 will be scored according to the scoring algorithm suggested 
by the authors of the questionnaires (Vickrey 1995). Scale scores will be generated by 
averaging the items within scales and transforming the mean scores linearly from 0 to 
100 possible scores, with higher scores indicating a better QOL. Physical and mental 
health composite scores will be generated by weighting the sum of selected scales to 
generate a simplified two-factor solution and the composite scores of the MSQOL-54. 
 
 
 


 
 
 
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Derivation of MSQOL-54 Composite Scores 
 
Two composite scores are defined for MSQOL-54 using the subscale scores defined in 
the table below. The MSQOL-54 Physical Health Composite score and the MSQOL-54 
Mental Health Composite Scores are calculated as a weighted-sum using the subscale 
scores and the weights defined in table below. If a subscale score is missing then it will 
not contribute to the Composite Score calculation (in effect, it is treated as a score of 0). 
 
Composite Score 
Subscale 
Weight for 
Composite 
Physical Health 
Physical Function 
0.17 
Health Perceptions 
0.17 
Energy 
0.12 
Role Limitations - Physical 
0.12 
Pain 
0.11 
Sexual Function 
0.08 
Social Function 
0.12 
Health Distress 
0.11 
Mental Health 
Health Distress 
0.14 
Overall Quality of Life 
0.18 
Emotional Well-being 
0.29 
Role Limitations - Emotional 
0.24 
Cognitive Function 
0.15 
 
5.2.2. 
Main analytical approach 
 
Primary analysis 
Endpoint/Variables 
• Change from baseline at Weeks 52 in Multiple Sclerosis Quality of Life 
(MSQOL)-54 Composite scores following treatment with HB-adMSCs or 
Placebo. 
ANCOVA Model Specification 
• To compare the HB-adMSCs to Placebo on Change from baseline to Week 52, a 
standard Analysis of Covariance (ANCOVA) model will be fitted 
• Terms fitted in the mixed effect model will include: 
• Primary endpoint efficacy measurements available at - Week 52 will be 
response variable in a linear mixed model using a variance-covariance residual 
matrix. 
• The model will include: 
• Fixed factors: treatment 
• Fixed strtatification factors: Multiple’s sclerosis severity (Mild disability 
(EDSS < 4) ; Moderate disability (EDSS > 4 and < 6.5)), Age (< 55 ; > 55) 
and Gender (Female ; Male) 


 
 
 
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• Covariate: baseline 
Model Checking and Diagnostics 
For the ANCOVA Model assumptions will be checked, and appropriate adjustments 
may be applied based on the data. 
Distribution assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residual and a plot of the residuals versus the 
fitted values (i.e., checking the normality assumption and constant variance assumption 
of the model respectively) to gain confidence that the model assumptions are 
reasonable. 
Non-parametric analyses, Mann-Whitney U (or Wilcoxon Rank-Sum) Test will be 
conducted if the normality assumptions do not hold. 
Results presentation 
Presentation of results from a statistical analysis model will include the estimated mean 
treatment effects (Least Square Means (LSMeans)) and estimated mean treatment 
differences will be presented together with two-sided 95% confidence intervals 
standard error for mean difference and p-value. 
 
Secondary analysis 
Endpoint/Variables 
Change from baseline in Multiple Sclerosis Quality of Life (MSQOL)-54 Composite 
scores following treatment with HB-adMSCs or Placebo at Week 4, Week 8, Week 16, 
Week 24, Week 32, Week 42 and Week 52. 
Repeated Measures Model Specification 
• To compare the HB-adMSCs to Placebo on Change from baseline, a Repeated 
measures analysis (RMA) model will be fitted 
• Terms fitted in the mixed effect model will include: 
• All primary endpoint efficacy measurements available at post-bseline at 
scheduled measurements will be response variable in a linear mixed 
model using an unstructured residual covariance matrix. 
• The model will include: 
• Fixed factors: treatment and visit  
• Fixed strtatification factors: Multiple's sclerosis severity (Mild disability 
(EDSS < 4) ; Moderate disability (EDSS > 4 and < 6.5)), Age (< 55 ; > 
55) and Gender (Female ; Male) 
• Covariate: baseline 


 
 
 
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• Furthermore, the model will include: 
• Interaction terms between treatment and visit 
Model Checking and Diagnostics 
For the Repeated Measures Analysis (RMA) Model assumptions will be checked, and 
appropriate adjustments may be applied based on the data. 
Distribution assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residual and a plot of the residuals versus the 
fitted values (i.e., checking the normality assumption and constant variance assumption 
of the model respectively) to gain confidence that the model assumptions are 
reasonable. 
Non-parametric analyses, Mann-Whitney U (or Wilcoxon Rank-Sum) Test will be 
conducted if the normality assumptions do not hold. 
Results presentation 
Presentation of results from a statistical analysis model will include the estimated mean 
treatment effects (Least Square Means (LSMeans)) and estimated mean treatment 
differences will be presented together with two-sided 95% confidence intervals 
standard error for mean difference and p-value. 
 
Additional analysis 
Summary analysis method 
To compare difference between baseline to Week 4, Week 8, Week 16, Week 24, Week 
32, Week 42 and Week 52, a paired t-test will be used for primary endpoint change 
from baseline Multiple Sclerosis Quality of Life (MSQOL)-54 Composite scores to 
check the statistical significance.  
To further evaluate if the improvements are clinically relevant, effect size of the 
treatment difference at Week 4, Week 8, Week 16, Week 24, Week 32, Week 42 and 
Week 52 will also be calculated for the efficacy endpoint using Cohen’s d calculation. 
Cohen’s d is a standardized measure of effect size (ES) that provides information on 
the amount of change in the outcome meaure relative to the variation within the 
measure. Cohen’s d is calculated as the difference between the HB-adMSCs mean 
score and Placebo mean scores divided by the standard deviations of the scores. An 
absolute effect size of <0.2 will be considered trivial, ³ 0.2 as small, ³0.5 as medium 
and >0.8 as large [1]. 
Cohen’s d =
!"#!$
(&'"(&'$)/$, where M1 and M2 are the Mean scores for HB-adMSCs and 
Placebo respectively, and SD1 and SD2 are the corresponding standard deviations. 
Results presentation 


 
 
 
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Secondary endpoints will be summarized using n, mean, confidence interval of mean, 
SD, median, minimum and maximum. And p-value for paired comparison will be 
displayed for all post-baseline visits. 
Normality checking 
Distribution assumptions used for the statistical analysis will be examined by obtaining 
a normal plot and Shapiro-Wilk Test. 
Non-parametric analyses, Wilcoxon signed-rank test will be conducted if the normality 
assumption does not hold. 
 
Supportive Statistical Analysis 
Bayesian Method 1 Endpoint/Variable 
Change from baseline at Weeks 52 in Multiple Sclerosis Quality of Life (MSQOL)-54 
Composite scores following treatment with HB-adMSCs or Placebo. 
Bayesian model specification 
Construct a linear model for each visit in order to model within-subject observation 
covariance structures by multivariate normal (MVN) distribution in the MCM 
procedure. 
 
For subject i on treatment j the model can be written as: 
 
CHGijk=β0 + β1 treatment + β2 baseline + β3strataEDSS + β4strataAge + 
β5strataGender + Ɛij  Ɛij ~ Normal (0, σ2) 
 
Where CHGij refers to change from baseline in subject i = 1, 2, ..., n indicator variable, 
which is intrinsically formed within PROC MCMC from the design matrix. 
 
Initial values of the MCMC chains will be selected at random. Seed for random number 
generation will be specified as "seed = 12345" with three MCMC chains of 8000 total 
iterations each (with 4000 of these discarded as burn-in iterations). The simulation size 
and number of burn-in interations can be updated during the convergence check. 
 
The choice of prior distribution for level two variances will follow Gelman’s 
recommendations from the literature. Models will use weakly informative priors to 
maximize the influence of the present data on posterior probabilities (PP). The non-
informative priors for the model parameters ~ Normal (0, σ2= 10) and 1/σ2 ~ Gamma 
(0.001, rate = 0.001) will be used. 
 
Models were evaluated via posterior probability guidelines in the literature, suggesting 
that PP = 75% to 90% indicates “moderate evidence,” PP = 91% to 96% indicates 
“strong evidence,” and PP ≥ 97% indicates “very strong to “extreme evidence.” 


 
 
 
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Consistent with prior research, a PP ≥75% (equivalent to a Bayes factor = 0.33 or 3.00) 
that an effect exists will be taken as a minimum threshold of evidence in favor of the 
alternative hypothesis. This probability was chosen to emphasize the value in 
identifying a signal for the effects of treatment group, time, and their interaction. 
 
The median, standard deviation, and 95% credible intervals (CrI) of the posterior 
distribution will be used to provide a point estimate and corresponding range of 
uncertainty for the magnitude of each predictor effect, including treatment group. 
Model Checking and Diagnostics 
Convergence diagnostics via scale reduction factors (Rhat), effective sample size, and 
posterior predictive distributions will be examined to ensure satisfaction of Bayesian 
modeiling assumptions, including Rhat < 1.01, sufficiently large effective sample size, 
and graphical inspection that the observed distribution of each outcome fell within the 
range of distributions produced by 1000 replications drawn from the posterior 
predictive distributions of the outcome. 
Adequate values for the number of MCM samples/thinning/number of burn-in samples 
should be chosen to ensure that the ratio Monte Carlo Standard Errors (MCSE) and 
standard deviation of the posterior distribution for all the parameters in the model as 
small as possible, typically close to 0.01. 
In addition, if possible, the number of tuning units and maximum number of tuning 
iterations may be increased to find a better proposal distribution for the model 
parameters, which in turn may reduce the MCSE/SD ratio. 
The Geweke diagnostics test checks whether the mean estimates have converged by 
comparing means from the early and latter part of the Markov chain using a z score t-
test. Large absolute values of the z-score statistic indicate rejection of the null 
hypothesis of no difference between the mean estimates obtained from the early and 
latter parts of the chain. 
The convergence diagnostics for all parameters in the Bayesian analysis will be 
visually checked by the trace plots. 
If the trace plots show apparent trend or the autocorrection plots show significant 
positive or negative correlation, number of iterations will be increased or 
reparameterization might be explored. 
Results presentation 
Presentation of results from the Bayesian statistical models will include the estimated 
conditional/marginal mean treatment effects and standard deviation. For all endpoints 
analysed statistically, estimated mean treatment differences will be presented together 
with 95% credible intervals and posterior probabilities. 
 


 
 
 
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Bayesian Method 2 Endpoint/Variable 
Change from baseline in Multiple Sclerosis Quality of Life (MSQOL)-54 Composite 
scores following treatment with HB-adMSCs or Placebo at Week 4, Week 8, Week 16, 
Week 24, Week 32, Week 42 and Week 52. 
Bayesian model specification 
Construct a linear model for each visit in order to model within-subject observation 
covariance structures by multivariate normal (MVN) distribution in the MCM 
procedure. 
 
For subject i on treatment j at Visit k, the model can be written as: 
 
CHGijk=β0 + β1 treatment + β2 baseline + β3 Visitk + β3strataEDSS + β4strataAge + 
β5strataGender + Ɛijk  Ɛijk ~ Normal (0, σ2) 
 
Where CHGijk refers to change from baseline in subject i = 1, 2, ..., n and Visitk for 
k= 1, 2, 3, 4, 5, 6 represents Week 4, Week 8, Week 16, Week 24, Week 32, Week 42 
and Week 52, respectively are indicator variables, which are intrinsically formed 
within PROC MCMC from the design matrix. 
 
Initial values of the MCMC chains will be selected at random. Seed for random number 
generation will be specified as "seed = 12345" with three MCMC chains of 8000 total 
iterations each (with 4000 of these discarded as burn-in iterations). The simulation size 
and number of burn-in interations can be updated during the convergence check. 
 
The choice of prior distribution for level two variances will follow Gelman’s 
recommendations from the literature. Models will use weakly informative priors to 
maximize the influence of the present data on posterior probabilities (PP). The non-
informative priors for the model parameters ~ Normal (0, σ2= 10) and 1/σ2 ~ Gamma 
(0.001, rate = 0.001) will be used. 
 
Models were evaluated via posterior probability guidelines in the literature, suggesting 
that PP = 75% to 90% indicates “moderate evidence,” PP = 91% to 96% indicates 
“strong evidence,” and PP ≥ 97% indicates “very strong to “extreme evidence.” 
Consistent with prior research, a PP ≥75% (equivalent to a Bayes factor = 0.33 or 3.00) 
that an effect exists will be taken as a minimum threshold of evidence in favor of the 
alternative hypothesis. This probability was chosen to emphasize the value in 
identifying a signal for the effects of treatment group, time, and their interaction. 
 
The median, standard deviation, and 95% credible intervals (CrI) of the posterior 
distribution will be used to provide a point estimate and corresponding range of 
uncertainty for the magnitude of each predictor effect, including treatment group. 
Model Checking and Diagnostics 
Convergence diagnostics via scale reduction factors (Rhat), effective sample size, and 
posterior predictive distributions will be examined to ensure satisfaction of Bayesian 


 
 
 
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modeiling assumptions, including Rhat < 1.01, sufficiently large effective sample size, 
and graphical inspection that the observed distribution of each outcome fell within the 
range of distributions produced by 1000 replications drawn from the posterior 
predictive distributions of the outcome. 
Adequate values for the number of MCM samples/thinning/number of burn-in samples 
should be chosen to ensure that the ratio Monte Carlo Standard Errors (MCSE) and 
standard deviation of the posterior distribution for all the parameters in the model as 
small as possible, typically close to 0.01. 
In addition, if possible, the number of tuning units and maximum number of tuning 
iterations may be increased to find a better proposal distribution for the model 
parameters, which in turn may reduce the MCSE/SD ratio. 
The Geweke diagnostics test checks whether the mean estimates have converged by 
comparing means from the early and latter part of the Markov chain using a z score t-
test. Large absolute values of the z-score statistic indicate rejection of the null 
hypothesis of no difference between the mean estimates obtained from the early and 
latter parts of the chain. 
The convergence diagnostics for all parameters in the Bayesian analysis will be 
visually checked by the trace plots. 
If the trace plots show apparent trend or the autocorrection plots show significant 
positive or negative correlation, number of iterations will be increased or 
reparameterization might be explored. 
Results presentation 
Presentation of results from the Bayesian statistical models will include the estimated 
conditional/marginal mean treatment effects and standard deviation. For all endpoints 
analysed statistically, estimated mean treatment differences will be presented together 
with 95% credible intervals and posterior probabilities. 
 
5.3. 
Secondary Endpoint(s) Analyses 
5.3.1. 
Efficacy Endpoints / Variables 
• Change from baseline at Week 52 in Total Expanded Disability Status Scale 
(EDSS) scores following treatment with HB- adMSCs or Placebo 
 
• Change from baseline at Week 52 in Barthel Index scores following treatment 
with HB- adMSCs or Placebo 
 
• Change from baseline at Week 52 in 9-Hole Peg Test scores following treatment 
with HB- adMSCs or Placebo 
 
• Change from baseline at Week 52 in Patient Health Questionnaire (PHQ-9) 
scores following treatment with HB-adMSCs or Placebo 


 
 
 
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Primary analysis 
 
Primary analysis of Repeated Measures Analysis (RMA) Model will be performed for 
above secondary efficacy endpoints above as given in the Section 5.2.2. 
 
Secondary analysis 
 
Secondary analysis of ANCOVA model will be perfomed to test the significance of 
treatment difference for secondary efficacy endpoints above as given in the Section 
5.2.2. 
 
Additional analysis 
 
Summary analysis will be perfomed to compare difference between baseline to Week 
4, Week 8, Week 16, Week 24, Week 32, Week 42 and Week 52, a paired t-test 
performed for secondary efficacy endpoints above as given in the Section 5.2.2. 
 
To further evaluate if the improvements are clinically relevant, effect size of the 
treatment difference at Week 4, Week 8, Week 16, Week 24, Week 32, Week 42 and 
Week 52, Cohen’s d will also be calculated for the secondary efficacy endpoints as given 
in the Section 5.2.2. 
 
5.3.2. 
Safety Analyses 
The safety analyses will be based on the Safety analysis set, unless otherwise specified. 
5.3.2.1. 
Extent of Exposure 
• Number of days of exposure to study drug will be calculated based on the formula: 
Duration of Exposure in Weeks = (Treatment stop date – Treatment start date)/7 
• Duration will be summarized by treatment group. Each subject will contribute 
duration of exposure to the treatment taken. 
• Participants who were randomized but not report a treatment start date will be 
categorised as having zero days of exposure. 
 
A listing and summary table of exposure will be created. 
 
The details of the planned displays are in programming specification document. 
 
5.3.2.2. 
Adverse Events 
AEs will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
A treatment emergent adverse event (TEAE) is defined as an event that has onset date 
on or after the first day of exposure to infusion treatment and on or before the first safety 
follow up at week 42/early withdrawal date. Here the first day of exposure is defined as 
the first day of exposure to infusion treatment. 


 
 
 
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Treatment emergent Adverse events TEAEs are summarized descriptively, whereas 
non-TEAEs are presented in listings. TEAE data will be displayed in terms of the 
number of subjects with at least one event (N), percentage of subjects with at least one 
event (%) and the number of events (E). 
Summaries of TEAEs and of serious AEs will be presented as an overview including all 
AEs, serious AEs, AEs by severity, AEs by relation to treatment, action to AEs and 
treatment advised, and outcome of AEs. 
Furthermore, summary tables based on system organ class and preferred terms are made 
for: 
• All TEAEs 
• Serious AEs 
• AEs leading to withdrawal of study 
• Incidence and risk of AEs of special interest (serious or nonserious), including 
thromboembolic events, peripheral events defined as, thromboembolism of the 
extremities, also infections and hypersensitivities. 
 
Individual adverse events will be listed. 
The details of the planned displays are in programming specification document. 
5.3.2.3. 
Clinical Laboratory data 
Laboratory evaluations will include the analyses of Biochemistry laboratory tests, 
Hematology laboratory tests and Urinalysis. The details of the planned displays are in 
programming specification document. 
All laboratory parameters, including numerical urine analysis parameters will be 
summarized descriptively. Categorical urine analysis results will be summarized using 
count and percentage based on subjects.  
Results of urine pregnancy test will be listed in individual subject data listings only. 
Individual laboratory evaluations will be listed. In addition, a listing containing 
individual subject laboratory values outside the normal reference ranges will be 
provided. 
Data recorded at unscheduled assessments will not be included in tables and figures but 
will be listed. 
 
5.3.3. 
Additional Safety Assessments 
The analyses of non-laboratory safety test results will include physical examination and 
vital signs.  
Physical Examination and Vital signs will be summarized using count and percentage 
based on subjects. The vital signs based on visit and change from baseline will be 
summarized using descriptive statistics. 
Individual Vital signs, Physical Examination evaluations will be listed. 
 


 
 
 
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The details of the planned displays are in programming specification document. 
 
5.4. 
Changes to Protocol Defined Analyses 
Analysis is planned as per protocol. No deviation from the planned protocol specified 
analysis. 
6. 
SAMPLE SIZE DETERMINATION 
Sample size consists of up to 24 subjects who have been diagnosed with Relapsing 
Remitting Multiple Sclerosis. 
7. 
SUPPORTING DOCUMENTATION 
7.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the “Safety” 
population. Screen failures will be summarized or listed based on the “Screened” 
population. A summary of the number of participants in each of the participant level 
analysis set will be provided. 
7.1.1. 
Subject Disposition 
A summary of the number and percentage of subjects who completed the study as well 
as those who withdrawn from the study will be provided by treatment. Reason of study 
withdrawn will be summarized by treatment.  
A summary of the study intervention status will be provided. This display will show the 
number and percentage of subjects who have completed the Week 52, as well as primary 
reasons for withdrawn. 
 
The study analysis set will be summarized in the subject disposition table. 
 
The details of the planned displays are in programming specification document. 
 
7.1.2. 
Demographic and Baseline Characteristics  
The demographic characteristics including, age, sex, ethnicity, race, height at baseline, 
weight at baseline, BMI at baseline will be summarized with descriptive statistics. In 
addition, the following categories will be summarized: 18-64, 65-84 and >=85 based on 
the randomized analysis set. 
 
Listings of demographic characteristics will also be produced. 
 
The details of the planned displays are in programming specification document. 
 
7.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 
 


 
 
 
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Page 19 of 24 
 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. 
 
The details of the planned displays are in programming specification document. 
 
7.1.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using WHO Drug Dictionary. 
Concomitant medications will be summarized as number and percentage of subjects. 
For classifying study phase for concomitant medications, use the following definition. 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before date of first dose of study 
medication. 
Concomitant 
Any medication that is not a prior 
 
Please refer to Section 7.2.6 for handling of missing and partial dates for concomitant 
medication. 
 
The details of the planned displays are in programming specification document. 
 
7.1.5. 
Study Intervention Exposure and Compliance 
A summary of Overall cumulative exposure to HB-adMSCs will be produced.  
 
The details of the planned displays are in programming specification document. 
 
7.2. 
Appendix 2 Data Derivation Rule 
 
7.2.1. 
Criteria for Potential Clinical Importance  
 
The potential clinical importance criteria are not defined this trial. A laboratory value 
that is outside the reference range is considered either high abnormal or low abnormal 
will be displayed based on lab normal range data. 
 
7.2.2. 
Study Period 
 
Adverse events will be classified according to the time of occurrence relative to the 
study intervention period. 
 
Treatment 
emergent 
Definition 
Y 
If event start date is not missing and is before date of first dose of study 
medication. 
N 
Any event started on or after date of first dose of study medication or event 
date is missing or partial 


 
 
 
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Statistical Analysis Plan 
CONFIDENTIAL 
 
 
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7.2.3. 
Study Day and Reference Dates 
 
Study Day 
• 
Study Day 1 is defined as the day the first dose was taken.  
• 
Study day >1 is calculated as the number of days from the date of the Study Day 1: 
• 
Ref Date = Missing → Study Day = Missing  
• 
Ref Date < Date of Study Day 1 → Study Day = Ref Date – Date of Study Day 1 
• 
Ref Data ≥ Date of Study Day 1 → Study Day = Ref Date – (Date of Study Day 1) 
+ 1 
 
7.2.4. 
Assessment Window 
 
For data summaries by visit, scheduled visits with nominal visit description will be 
displayed. Unscheduled visits will not be displayed or slotted into a visit window. While 
in the baseline derivation or post-baseline worst scenarios are derived, unscheduled 
visits are considered. All unscheduled visits will be displayed in listings, as appropriate. 
 
7.2.5. 
Multiple measurements at One Analysis Time Point 
 
For lab tests on a study day, if more than one assessment is taken on the same day, the 
test from the latest non-missing lab measurements will be used for the analysis. All lab 
measurements will be displayed in the listings, as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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7.2.6. 
Handling of Missing and Partial Dates 
 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in participant listing 
displays. 
Adverse Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the 
following conventions: 
Missing start day 
If study intervention start date 
is missing (i.e, subject did not 
start the study medication), 
then set start date = 1st of 
month. 
 
Else if study intervention start 
date is not missing: 
 
• 
If month and year of start 
date = month and year of 
study intervention start 
date, then  
o If stop date contains a 
full date and stop date 
is earlier than study 
intervention start date, 
then set start = 1st of 
month. 
o Else set start date = 
study 
intervention 
start date. 
 
• 
Else set start date = 1st of 
month 


 
 
 
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Statistical Analysis Plan 
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Element 
Reporting Detail 
Missing start day and month 
If study intervention start date 
is missing (ie., subject did not 
start study medication), then 
set start date = January 1. 
 
• 
Else if study intervention 
start date is not missing: 
o If year of start date = 
year 
of 
study 
intervention start date, 
then  
§ 
If stop date contains 
a full date and stop 
date is earlier than 
study intervention 
start date, then set 
start date = January 
1. 
o Else set start date = 
study intervention start 
date. 
Else set start date = January 1. 
Missing end day 
A ‘28/29/30/31’ will be used 
for the day (dependent on the 
month and year) 
Missing end day and month 
No imputation 
Completely missing start/end 
date 
No imputation 
 


 
 
 
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HBMS01 
 
Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Page 23 of 24 
 
Element 
Reporting Detail 
Concomitant 
Medications 
• 
Partial dates for any concomitant medications recorded in the CRF 
will be imputed using the following convention: 
Missing start day 
If study intervention start date 
is missing (i.e, subject did not 
start the study medication), 
then set start date = 1st of 
month. 
 
Else if study intervention start 
date is not missing: 
 
• 
If month and year of start 
date = month and year of 
study intervention start 
date, then  
o If stop date contains a 
full date and stop date 
is earlier than study 
intervention start date, 
then set start = 1st of 
month. 
o Else set start date = 
study 
intervention 
start date. 
 
• 
Else set start date = 1st of 
month 


 
 
 
Hope Biosciences Research Foundation 
HBMS01 
 
Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Page 24 of 24 
 
Element 
Reporting Detail 
Missing start day and month 
If study intervention start date 
is missing (ie., subject did not 
start study medication), then 
set start date = January 1. 
 
• 
Else if study intervention 
start date is not missing: 
o If year of start date = 
year 
of 
study 
intervention start date, 
then  
§ 
If stop date contains 
a full date and stop 
date is earlier than 
study intervention 
start date, then set 
start date = January 
1. 
o Else set start date = 
study intervention start 
date. 
Else set start date = January 1. 
Missing end day 
A ‘28/29/30/31’ will be used 
for the day (dependent on the 
month and year) 
Missing end day and month 
A ‘31’ will be used for the day 
and ‘Dec’ will be ised for the 
month 
Completely missing start/end 
date 
No imputation 
 
 
8. 
REFERENCES 
Hope Biosciences protocol number HBMS01 A Randomized, Double-Blind, Single 
Center, Phase 2, Efficacy and Safety Study of Autologous HB-adMSCs vs Placebo for 
the Treatment of Patients with Multiple Sclerosis 
 
Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of 
life measure for multiple sclerosis. Qual Life Res. 1995 Jun;4(3):187-206. doi: 
10.1007/BF02260859. PMID: 7613530.