Clinical trial NCT03866200
Conditions: Pseudoachondroplasia
Keywords: resveratrol joint pain
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2019-06-29; Completion date: 2020-10-28
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine if self-administered oral resveratrol can dampen joint pain for individuals with pseudoachondroplasia compared to placebo. Another goal of this study is to evaluate side effects in this population.

Detailed description:

Arms: arm 1: Participants first received Resveratrol 125 mg/day or 5 ml daily for 90 days. After a washout period of 30 days, they then received Placebo 5ml daily for 90 days. arm 2: Participants first received Placebo 5ml daily for 90 days. After a washout period of 30 days, they then received Resveratrol 125 mg/day or 5 ml daily for 90 days.
Interventions: intervention 1: resveratrol intervention 2: Placebo
Intervention descriptions: intervention 1: 125 mg/day or 5 ml once per day for 90 days intervention 2: 5 ml once per day for 90 days

Protocol documents:
Prot_SAP_000.pdf: 
IRB APPROVAL DATE: 05/15/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resveratrol trial for relief of pain in pseudoachondroplasia 
NCT03866200 
 
Version Date: 05/15/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB APPROVAL DATE: 05/15/2020 
 
Resveratrol trial for relief of pain in pseudoachondroplasia 
 
Protocol Identifying Number: HSC-MS-17-0573 
Principal Investigator: Jacqueline T. Hecht,  PhD; Karen L. Posey, PhD 
Co-Investigator: David F.Rodriguez-Buritica, MD 
IND Sponsor-Investigator: Karen L. Posey, PhD 
Funded by: NA 
Version Number: Version 1.4—04/01/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-17-0573 


IRB NUMBER: HSC-MiiS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
 
Table of Contents 
LIST OF ABBREVIATIONS ................................................................................................................................................ 1 
STATEMENT OF COMPLIANCE ....................................................................................................................................... 1 
PROTOCOL SUMMARY ................................................................................................................................................... 1 
SCHEMATIC OF STUDY DESIGN ...................................................................................................................................... 2 
1 
KEY ROLES ......................................................................................................................................................... 2 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................................. 3 
2.1 
Background Information ........................................................................................................................ 3 
2.2 
Rationale ................................................................................................................................................ 3 
2.3 
Potential Risks and Benefits ................................................................................................................... 4 
2.3.1 
Known Potential Risks ......................................................................................................... 4 
2.3.2 
Known Potential Benefits ................................................................................................... 4 
3 
OBJECTIVES AND PURPOSE ............................................................................................................................... 4 
4 
STUDY DESIGN AND ENDPOINTS ....................................................................................................................... 4 
4.1 
Description of the Study Design ............................................................................................................. 4 
4.2.1 
Primary Endpoint ................................................................................................................ 4 
4.2.2 
Secondary Endpoints .......................................................................................................... 4 
4.2.3 
Exploratory Endpoints ........................................................................................................ 5 
5 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................................................................ 5 
5.1 
Participant Inclusion Criteria .................................................................................................................. 5 
5.2 
Participant Exclusion Criteria.................................................................................................................. 5 
5.3 
Strategies for Recruitment and Retention ............................................................................................. 5 
5.4 
Participant Withdrawal or termination .................................................................................................. 5 
5.4.1 
Reasons for Withdrawal or Termination ............................................................................ 5 
5.4.2 
Handling of Participant Withdrawals or termination ......................................................... 5 
5.5 
Premature Termination or Suspension of Study .................................................................................... 6 
6 
STUDY AGENT .................................................................................................................................................... 6 
6.1 
Study Agent(s) and Control Description ................................................................................................. 6 
6.1.1 
Acquisition .......................................................................................................................... 6 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ........................................................... 6 
6.1.3 
Product Storage and Stability ............................................................................................. 6 
6.1.4 
Preparation ......................................................................................................................... 7 
6.1.5 
Dosing and Administration ................................................................................................. 7 
6.1.6 
Route of Administration ..................................................................................................... 7 
6.1.7 
Starting Dose and Dose Escalation Schedule ...................................................................... 7 
6.1.8 
Dose Adjustments/Modifications/Delays ........................................................................... 7 
6.1.9 
Duration of Therapy ............................................................................................................ 7 
6.1.10 
Tracking of Dose ................................................................................................................. 7 
6.1.11 
Device Specific Considerations ........................................................................................... 7 
6.2 
Study agent Accountability Procedures ................................................................................................. 8 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................................................... 8 
7.1 
Study Procedures/Evaluations ............................................................................................................... 8 
7.1.1 
Study specific procedures ................................................................................................... 8 
7.1.2 
Standard of care study procedures..................................................................................... 8 
7.2 
Laboratory Procedures/Evaluations ....................................................................................................... 8 
7.2.1 
Clinical Laboratory Evaluations ........................................................................................... 8 
7.2.2 
Other Assays or Procedures ................................................................................................ 8 


IRB NUMBER: HSC-MiiS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
 
7.2.3 
Specimen Preparation, Handling, and Storage ................................................................... 8 
7.2.4 
Specimen Shipment ............................................................................................................ 8 
7.3 
Study Schedule ....................................................................................................................................... 8 
7.3.1 
Screening…......................................................................................................................... 9 
7.3.2 
Enrollment/Baseline ........................................................................................................... 9 
7.3.3 
Follow-up9 
7.3.4 
Final Study Visit ................................................................................................................... 9 
7.3.5 
Early Termination Visit ........................................................................................................ 9 
7.3.7 
Schedule of Events Table .................................................................................................. 10 
7.4 
Justification for Sensitive Procedures ................................................................................................... 11 
7.5 
Concomitant Medications, Treatments, and Procedures ..................................................................... 11 
7.5.1 
Precautionary Medications, Treatments, and Procedures ............................................... 11 
7.6 
Prohibited Medications, Treatments, and Procedures ......................................................................... 11 
7.7 
Prophylactic Medications, Treatments, and Procedures ...................................................................... 11 
7.8 
Rescue Medications, Treatments, and Procedures .............................................................................. 11 
7.9 
Participant Access to Study Agent At Study Closure ............................................................................ 11 
8 
ASSESSMENT OF SAFETY ................................................................................................................................. 11 
8.1 
Specification of Safety Parameters ....................................................................................................... 11 
8.1.1 
Definition of Adverse Events (AE) ..................................................................................... 11 
8.1.2 
Definition of Serious Adverse Events (SAE) ....................................................................... 12 
8.1.3 
Definition of Unanticipated Problems (UP) ...................................................................... 12 
8.2 
Classification of an Adverse Event ........................................................................................................ 12 
8.2.1 
Severity of Event ............................................................................................................... 12 
8.2.2 
Relationship to Study Agent ............................................................................................. 12 
8.2.3 
Expectedness .................................................................................................................... 13 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up ...................................................... 13 
8.4 
Reporting Procedures ........................................................................................................................... 13 
8.4.1 
Adverse Event Reporting .................................................................................................. 13 
8.4.2 
Serious Adverse Event Reporting ...................................................................................... 13 
8.4.3 
Unanticipated Problem Reporting .................................................................................... 14 
8.4.4 
Events of Special Interest .................................................................................................. 14 
8.4.5 
Reporting of Pregnancy .................................................................................................... 14 
8.5 
Study Halting Rules ............................................................................................................................... 14 
8.6 
Safety Oversight ................................................................................................................................... 14 
9 
CLINICAL MONITORING ................................................................................................................................... 14 
10 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 14 
10.1 
Statistical and Analytical Plans ............................................................................................................. 14 
10.2 
Statistical Hypotheses .......................................................................................................................... 15 
10.3 
Analysis Datasets .................................................................................................................................. 15 
10.4 
Description of Statistical Methods ....................................................................................................... 15 
10.4.1 
General Approach ............................................................................................................. 15 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ..................................................................... 15 
10.4.3 
Analysis of the Secondary Endpoint(s).............................................................................. 16 
10.4.4 
Safety Analyses ................................................................................................................. 16 
10.4.5 
Adherence and Retention Analyses .................................................................................. 16 
10.4.6 
Baseline Descriptive Statistics ........................................................................................... 16 


IRB NUMBER: HSC-MiiS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
 
10.4.7 
Planned Interim Analyses ................................................................................................. 16 
10.4.9 
Multiple Comparison/Multiplicity .................................................................................... 17 
10.4.10 
Tabulation of Individual Response Data ........................................................................... 17 
10.4.11 
Exploratory Analyses ........................................................................................................ 17 
10.5 
Sample Size ........................................................................................................................................... 17 
10.6 
Measures to Minimize Bias .................................................................................................................. 17 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .......................................................... 17 
10.6.2 
Evaluation of Success of Blinding ...................................................................................... 18 
10.6.3 
Breaking the Study Blind/Participant Code ...................................................................... 18 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............................................................ 18 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................................. 18 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................................... 18 
13.1 
Ethical Standard ................................................................................................................................... 18 
13.2 
Institutional Review Board ................................................................................................................... 18 
13.3 
Informed Consent Process ................................................................................................................... 19 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants .............. 19 
13.3.2 
Consent Procedures and Documentation ......................................................................... 19 
13.4 
Participant and data Confidentiality ..................................................................................................... 19 
13.4.1 
Research Use of Stored Human Samples,Specimens or Data ........................................... 19 
13.5 
Future Use of Stored Specimens .......................................................................................................... 20 
14 
DATA HANDLING AND RECORD KEEPING ........................................................................................................ 20 
14.1 
Data Collection and Management Responsibilities .............................................................................. 20 
14.2 
Study Records Retention ...................................................................................................................... 20 
14.3 
Protocol Deviations .............................................................................................................................. 20 
14.4 
Publication and Data Sharing Policy ..................................................................................................... 20 
15 
STUDY ADMINISTRATION ................................................................................................................................ 20 
15.1 
Study Leadership .................................................................................................................................. 20 
16 
CONFLICT OF INTEREST POLICY ....................................................................................................................... 20 
17 
LITERATURE REFERENCES ................................................................................................................................ 21 
APPENDIX ..................................................................................................................................................................... 25 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
  LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
COMP 
Cartilage Oligomeric Matrix Protein 
DCC 
Data Coordinating Center 
DHHS 
DHHS Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
FDA 
FDA Food and Drug Administration 
GCP 
GCP Good Clinical Practice 
GLP 
GLP Good Laboratory Practices 
HIPAA 
HIPAA Health Insurance Portability and Accountability Act 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
MOP 
Manual of Procedures 
NIH 
NIH National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PSACH 
Pseudoachondroplasia 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
CI 
Co Investigator 
 
  STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the following (use 
applicable regulations depending on study location and sponsor requirements; examples follow): United States (US) 
Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 
CFR Part 312, and/or 21 CFR Part 812) ICH E6 
 
All key personnel (all individuals responsible for the design and conduct of this trial) have completed Human 
Subjects Protection Training. 
 
 
   PROTOCOL SUMMARY 
 
Title: 
Trial of Resveratrol for Pseudoachodroplasia Pain 
Précis: 
This is a cross over designed study to determine if self-administered oral resveratrol 
(90 days) can dampen joint pain for individuals with pseudoachondroplasia 
compared to placebo (90 days) as measured by daily pain logs. 
Objectives: 
To determine if resveratrol reserveage liquid lessens joint pain in  individuals with 
pseudoachondroplasia. 
 
 
Endpoint 
Self-reported pain as ascertained by a 11-point pain scale from 0 to 10. 
Population: 
Pseudoachondroplasia patients aged 18 to 70 yrs (details below) 
Phase: 
IIA (“proof of concept” study) 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
Number of Sites enrolling 
participants: 
Description of Study Agent 
: 
1 
 
Resveratrol Reserveage liquid super berry blend 225 mg + Pro-longevity factors 
blend 130 mg including 125 mg trans-resveratrol 
Study Duration: 
5 yrs 
Participant Duration: 
210 days 
 
 
Medical Monitor: 
Diane Novy, PhD, Professor 
MD Anderson Cancer Center 
MD Anderson Boulevard 
Houston, TX 77030 
 
 
Principal Investigators (PIs): 
Jacqueline T. Hecht,  PhD, Professor 
McGovern Medical School at The University of Texas Health at Houston 
 
 
Houston TX 77030 
SCHEMATIC OF STUDY  DESIGN 
1 
KEY ROLES 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
 
Jacqueline.T.Hecht@uth.tmc.edu 
 
Karen L. Posey, PhD, Assistant Professor 
McGovern Medical School at The University of Texas Health at Houston 
 
Houston TX 77030 
713 500 5786 
Karen.Posey@uth.tmc.edu 
 
David Rodriguez-Buritica, MD, Assistant Professor 
McGovern Medical School at The University of Texas Medical School at Houston 
 
Houston, Texas 77030 
 
 
 
Biostatistician: 
Syed S. Hashmi, M.D., M.P.H., Ph.D. 
McGovern Medical School at The University of Texas Health at Houston 
 
Houston TX 77030 
 
 
 
Study Coordinator: 
Elena Serna 
McGovern Medical School at The University of Texas Health at Houston 
 
Houston TX 77030 
 
 
 
 
 
Pseudoachondroplasia  (PSACH),  a  severe  short-limb  dwarfing  condition,  results  from  mutations  that      cause 
misfolding of the cartilage oligomeric matrix protein (COMP). Accumulated COMP in growth plate chondrocytes 
activates cellular stress that leads to inflammation and oxidative stress, ultimately causing chondrocyte death. The 
most debilitating features of the disorder is childhood joint pain and severe early-onset osteoarthritis. The only 
treatments for this pain are sporadic NASAID administration and joint replacement. We have shown that resveratrol 
dampens chondrocyte inflammation in a mouse model of the disorder. Given the lack of specific treatment for 
PSACH, the positive results with resveratrol in the mouse model and the low risk of resveratrol treatment, we 
propose to test resveratrol to treat joint pain in PSACH. 
 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC  RATIONALE 
2.1 
BACKGROUND INFORMATION 
2.2 
RATIONALE 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
We have shown, in a mouse model of PSACH, that resveratrol reduces chondrocyte inflammation and improves the 
health and longevity of chondrocytes1. This work was the first and only therapeutic approach shown to mitigate both 
the chondrocyte and long-bone pathology of PSACH in a mouse model and suggests that reducing inflammation and 
oxidative stress early in the disease process with resveratrol may be a novel approach to treat this disorder. 
Additionally, other researchers have shown that resveratrol reduces joint damage in mouse models of arthritis2-9. 
Taken together these observations suggest that resveratrol may be beneficial for PSACH joint pain. In addition, 
resveratrol is available over the counter and has not been associated with major adverse events suggesting that the 
risk associated with resveratrol are low. 
 
 
Four clinical trials have shown mild to moderate adverse gastrointestinal side effects associated with high levels of 
resveratrol 0.5- 5 g/day.10-12and Resveratrol for Alzheimer's disease at clinicaltrials.gov. The longest safety study was 
a 52 week phase II study of dosages up to 2 g/day for adults, the incidence of nausea and diarrhea were no different 
between placebo and resveratrol groups13,14. This phase II trial of 119 participants administered pure synthetic 
resveratrol 500 mg orally once daily with a dose escalation by 500-mg increments every 13 weeks until a final dose 
of 1000 mg twice daily was reached for the final 13 weeks concluded “Resveratrol (1) is detectable in cerebrospinal 
fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves 
blood–brain barrier integrity, and (5) modulates the CNS immune response 13,14”. This 52 week safety trial shows 
that resveratrol is safe to use in humans for an extended period of time at dosages above those used in our study. 
Additionally, resveratrol is available over the counter and has not been associated with major adverse events, 
suggesting that the risk associated with resveratrol is low. Previous studies in adults have used resveratrol dosages 
ranging from 40 mg - 5 g 10-12,15-31. There are at least 100 resveratrol clinical trials and many studies did not show or 
discuss adverse events 15-31. Four clinical trials showed mild to moderate adverse gastrointestinal side effects 
associated 
with 
high 
levels 
of 
resveratrol 
0.5- 
5 
g 
per 
day 
10-12 
and 
(https://clinicaltrials.gov/ct2/show/results/NCT01504854?term=resveratrol&cond=Alzheimer+Disease&rank=1&se 
ct=X430156#othr). Our study dosage at 125 mg/day for adults is far below this range 
 
Category 
Summary of findings 
Reference 
Common adverse events 
- 
mild to moderate adverse gastrointestinal side 
effects 12,10,11 
- 
In the largest (n = 119), longest (52 weeks), and 
highest-dose (ending with 2 g by mouth daily) 
human study of resveratrol to date, a total of 104 
participants completed the phase II study14. 
Inclusion criteria individuals >49 years old with a 
diagnosis of mild-to-moderate dementia due to 
AD, with stable medications and medically stable. 
No differences were found between the 
resveratrol and placebo-treated groups in terms 
of safety and tolerability, with the only 
exception being weight loss in the resveratrol- 
treated group. The most common reported AEs 
were nausea and diarrhea, with 42% reported in 
the resveratrol group versus 33% in the placebo 
group. The difference between groups was not 
statistically significant different. The high 
background of gastrointestinal AEs is likely due to 
concomitant treatment with a cholinesterase 
12,10,11,14 
2.3 
POTENTIAL RISKS AND  BENEFITS 
2.3.1 
KNOWN POTENTIAL RISKS 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
inhibitor approved for Alzheimer disease. Weight 
loss in the resveratrol-treated group may be due 
to enhanced mitochondrial biogenesis mediated 
by SIRT1. 
Serious adverse events 
- 
Renal failure with SRT501 (a micronized oral 
formulation of resveratrol) and bortezomid 12 
- 
fever and bicytopenia 14 
12,14 
Expected adverse events 
- 
nausea and diarrhea 
12,10,11,14 
No adverse events discussed 
15-31 
Most studies did not show or discuss adverse events 15-31. Our study dosage at 125 mg/day for adults are far below 
these levels of 0.5 to 5 g per day which were associated with gastrointestinal distress. 
 
Numerous in vitro and in vivo studies have shown antioxidant and anti-inflammatory properties are associated with 
resveratrol administration32. Since oxidative stress and inflammation play a important role in PSACH chondrocyte 
pathology, these antioxidant and anti-inflammatory properties may reduce join pain in PSACH. 
 
To determine whether resveratrol treatment is  effective in reducing pain in PSACH. 
 
 
The study has a 2x2 crossover design.  Participants will take either the placebo or resveratrol for 90 days   followed 
by a 30 day washout period and the placebo or resveratrol for the last 90 days. 30 day washout period was choosen 
in order to eliminate any carry over from reseveratrol as it is recommended to avoid resveratrol 2 weeks prior to 
surgery suggesting that carry over could potentially be as long as 2 weeks (http://www.webmd.com/vitamins- 
supplements/ingredientmono-307-resveratrol.aspx?activeingredientid=307; 
http://ww5.komen.org/BreastCancer/Resveratrol.html). Participants will be mailed a 30 or 90 day (for international 
participants) supply of placebo or resveratrol which they will receive 5 days before the end of each 30 day period 
(not applicable for international participants). Participants will keep daily pain log of pain and activity levels during 
the entire 210 day study period. We recognize that this is a long period of time however this population is highly 
motivated because 1) their pain is not systematically treated, 2) currently available over the counter NSAIDs, 
frequently used to control pain, cause gastrointential issues when used for prolonged periods and 3) participants 
reached through Little People of America and the PSACH facebook page are actively seeking solutions to control 
pain. This is being co-ordinated by a single center and will enroll 30 PSACH individuals. Because this is a rare 
condition, participants from 18 years - to 70 years will be enrolled. 
 
4.2.1 
PRIMARY ENDPOINT 
Self-reported pain will be obtained from all study subjects using the Numeric Pain Rating Scale to score the subject’s 
pain on a 0 to 10 scale. This scale has been validated and widely used33-38. A pain level will be assessed with 
enrollment in order to assure the participant has pain. An additional assessment will take place at the first visit (day 
0). Pain will then be ascertained daily (including during the “washout” period between the two intervention periods) 
through a daily pain log kept by participants. The pain logs will be requested from participants at each follow-up visit 
and at the end of each month in the treatment periods, and data from the pain logs will be compiled and  analyzed 
2.3.2 
KNOWN POTENTIAL BENEFITS 
3 
OBJECTIVES AND PURPOSE 
4 
STUDY DESIGN AND  ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY  DESIGN 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
at the start and end of each of the two treatment periods (on days 0, 90, 120, and 210). Monthly pain averages will 
be compared to baseline. 
The primary endpoint will be change in pain score between baseline and monthly average pain scores. The pain 
score on each day of month one will be averaged to obtain the average pain score for month one, and the same will 
be done for months two and three, and each of the monthly average scores for resveratrol and placebo periods will 
be compared to baseline. 
 
4.2.2 
SECONDARY ENDPOINTS 
Monthly, health related quality of life scores (HRQoL) will be obtained and the 36-Item Short Form Health Survey 
(SF-36). These instruments have been validated. For the secondary outcome measure, baseline HRQoL will be 
compared to the 30, 60, and 90 day HRQoL scores. 
 
NA 
 
 
1. The diagnosis of PSACH is based on clinical assessment either in person or by photographic review by  skeletal 
dysplasia specialist (JTH), 
2. Healthy beyond PSACH associated complications, 
3. Age at enrollment between 18 years to 70 years. 
4. Baseline pain level of 2 or higher on 10 point scale. 
 
1. Current use of resveratrol 
2. Current use of blood thinners, lovastatin, ketoconazole, itraconazole, fexofenadine and triazolam. 
3. Other non-PSACH realted health conditions, e.g. cancers. 
4. Pregnancy or breastfeeding. 
5. Women of childbearing age not using adequate contraception methods known to prevent pregnancy during the 
study. 
6. Participation in another clinical study and/or using investigational agents. 
7. Use of NSAIDs or aspirin. 
8. Current use of Alfentanil, Cyclosporine, Dihydroergotamine, Dofetilide, Ergotamine, Fentanyl, Flibanserin, 
Oxycodone, Pimavanserin, Pimozide, Quinidine, Saquinavir, Sirolimus, Tacrolimus, Temsirolimus, Theophylline, 
Tizanidine, Thioridazine, Fosphenytoin, Phenytoin or Warfarin. 
9. Age 17 years or less. 
10. Platelet count below 50,000 per l on baseline CBC. 
 
Recruitment will be conducted at Little People of America convention (n=300 PSACH members) and the PSACH blog 
(Facebook page: “Pseudoachondroplasia Dwarfish – and growing!!!” Closed group with 211 members). We will be 
recruiting International participants that contact us with interest in the study or that international colleagues refer 
to us. This recruitment strategy reaches out to the most active population in order to recruit motivated participants 
4.2.3 
EXPLORATORY ENDPOINTS 
5 
STUDY ENROLLMENT AND  WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
5.3 
STRATEGIES FOR RECRUITMENT AND  RETENTION 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
that will complete the 7 month study. Monthly calls to participants to assess compliance and record keeping as well 
as any adverse events will be done to increase retention. 
 
 
 
Participants are free to withdraw from the study at any time upon notification to the PI or study coordinator via 
phone or written request via email or postal mail An investigator may terminate participation in the study if: 
a. 
Any clinical adverse event (AE) or other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant. 
b. The participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation. 
 
Participants who choose to withdraw or are withdrawn due to an AE or exclusion critera must return the unused 
portion of study materials to the study coordinator. All mailing/communication costs will be paid by the study. 
 
All participants withdrawn/discontinued will be followed for 1 month to make sure that no AEs have developed after 
withdrawal from the study. If a participant was withdrawn due to AEs, they will be advised to seek medical help with 
their primary care physician. Those costs are not covered by this study. 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the study PI to IND 
sponsor. If the study is prematurely terminated or suspended, the PI will promptly inform the IRB and will provide 
the reason(s) for the termination or suspension 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants; 
• 
Demonstration of efficacy that would warrant stopping; 
• 
Insufficient compliance to protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable; 
• 
Determination of futility. 
A suspended study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the IRB and/or FDA 
 
 
 
Resveratrol liquid manufactured by Reserveage Nutrition will be purchased by the study.      Placebo formulated by 
John Yoo, Pharmacist at The Compounding Shop (http://mycompoundingshop.com/) will be purchased. 
5.4 
PARTICIPANT WITHDRAWAL OR  TERMINATION 
5.4.1 
REASONS FOR WITHDRAWAL OR  TERMINATION 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR   TERMINATION 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF  STUDY 
6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL  DESCRIPTION 
6.1.1 
ACQUISITION 


Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
 
 
 
 
Resveratrol liquid manufactured by Reserveage Nutrition will be tinted to match placebo color and repackaged   in 
standard amber plastic bottle and relabeled so that the study participants will not know whether the compound is 
placebo or resveratrol. Placebo formulated to taste similar to the resveratrol liquid and be similar in appearance will 
be packaged in standard amber plastic bottle and labeled so that the study participants will not know whether the 
compound is placebo or resveratrol. Bottles will be labeled with particiapants name. This work will be performed by 
The Compounding Shop at 11851 Wilcrest Dr, Houston, TX 77031; Phone: 281-495-2230; Fax: 281- 495-2232. 
 
Resveratrol and placebo are stable at room temperature for extended periods of time but the manufacturer 
recommends storage in the refrigerator after opening. The participants will be instructed to store the opened 
supplement in the refrigerator. 
 
As mentioned in section 6.1.2, resveratrol liquid will be tinted to match placebo color prior to repackaging.        The 
packaged supplement and placebo are ready to be administered as is when supplied to the participants and do not 
require any futher preparation or dilution. 
 
 
Oral liquid 
 
N/A 
 
N/A 
 
90 days each of either placebo or resveratrol, with a month (30 days) of no medication in between the crossover 
administration. 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND  LABELING 
Based  on  the  manufacturer’s  recommendation,  the     adult 
dosage is 125 mg/day or 5 ml of resveratrol reserveage liquid 
(http://reserveage.com/product/resveratrol-cellular-age- 
defying-tonic/). 
Four   clinical   trials   have   shown mild  to 
moderate adverse gastrointestinal side effects associated with 
high levels of resveratrol 0.5- 5 g/day.10-12,15-31 and Resveratrol 
for Alzheimer's disease at clinicaltrials.gov. While at least 
many other studies did not show or discuss adverse events 15- 
31. Our study dosages at 125 mg/day for adults are far  below 
these levels. 
Self aministration for participants. Participants should take 
study medication 30 min prior to breakfast. 
6.1.6 
ROUTE OF ADMINISTRATION 
6.1.3 
PRODUCT STORAGE AND  STABILITY 
6.1.4 
PREPARATION 
6.1.5 
DOSING AND ADMINISTRATION 
6.1.7 
STARTING DOSE AND DOSE ESCALATION  SCHEDULE 
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
6.1.9 
DURATION OF THERAPY 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
 
Doses are administered by the participants with 30 day supply mailed out monthly or 90 day supply for international 
participants. 
 
N/A 
 
Resveratrol and placebo will be received by the study team from The Compounding Shop at 11851 Wilcrest Dr., 
Houston, TX 77031; Phone: 281-495-2230; Fax: 281-495-2232 and stored at room temperature in a secure location. 
Study coordinator will be responsible for mailing resveratrol and placebo to participants based on their randomized 
arm and a log will be kept recording drug/placebo identifier and to whom it is mailed. Study coordinator will be 
responsible for collecting the unused supplement and placebo from participants. 
 
 
• 
All potential participants will submit photos to confirm their PSACH diagnosis either by directly depositing 
photos into a secured encrypted server or via US mail (to be scanned and put into our secure data base and 
subsequently shredded. 
• 
Medical history will be obtained by interview to confirm diagnosis of PSACH and to exclude those taking 
exclusion medications resveratrol, blood thinners, lovastatin, ketoconazole, itraconazole, fexofenadine, 
triazolam, Alfentanil, Cyclosporine, Dihydroergotamine, Dofetilide, Ergotamine, Fentanyl, Flibanserin, 
Oxycodone, Pimavanserin, Pimozide, Quinidine, Saquinavir, Sirolimus, Tacrolimus, Temsirolimus, 
Theophylline, Tizanidine, Thioridazine, Fosphenytoin, Phenytoin, or Warfarin. This information will be 
ascertained by the study staff over the phone and the participants will be asked to read the names of the 
medications and the dosages off the medicine containers. Information on medications will be collected for 
All medications the participant is on (both prescription and OTC). Exclusions will be made if any of the 
medications mentioned above are being used. 
• 
Pain will be assessed to ensure that participants have pain to enroll in the study. 
• 
For this 2X2 crossover design with two periods, patients will be randomized to one of two sequences, 
resveratrol/placebo or placebo/resveratrol. Those randomized to resveratrol/placebo will be given 
resveratrol in the first period and placebo in the second and vice versa for those randomized to to the 
placebo/resveratrol sequence. Randomization will be carried out by our biostatistician so that investigators 
evaluating outcomes, along with participants, are blinded. 
• 
Once enrolled into the study and randomized, a parcel will be mailed to the participants including all study 
materials including first month’s study drug supply, study forms and pain logs. 
• 
Monthly phone calls will be used to assess of adherence to protocol and will be logged into the study 
logbook by study staff. These phone calls will also include ascertainment of any changes to medications and 
diagnosis of any new health condition or pregnancy. 
• 
Patient-reported daily pain logs will be mailed or emailed to study co-ordinator on a monthly basis. 
• 
Platelet count below 50,000 per μl will result in exlusion from the study as this increases risk of bleeding 
with injury. A normal platelet count is around 140,000 to 450,000 platelets per microliter (μl) of blood. 
When the number of platelets is low, this concentration reduces. Women normally experience a platelet 
count that varies slightly during the menstrual cycle and can fall near the end of pregnancy. The risk of 
bleeding increases as the platelet count drops, but bleeding problems are unlikely unless the count is less 
than 80,000-100,000 platelets per μl. 
6.1.10   TRACKING OF DOSE 
6.1.11   DEVICE SPECIFIC CONSIDERATIONS 
6.2 
STUDY AGENT ACCOUNTABILITY  PROCEDURES 
7 
STUDY PROCEDURES AND  SCHEDULE 
7.1.1 
STUDY SPECIFIC PROCEDURES 
7.1 
STUDY PROCEDURES/EVALUATIONS 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
The following platelet counts carry the risk of serious bleeding: 
Between 20,000 and 50,000 per μl: There is more risk of bleeding when injured. 
Less than 20,000 per μl: Bleeding happens even without injury. 
Below 10,000 platelets per μl: Spontaneous bleeding can be severe and a risk to life. 
 
N/A 
 
 
 
NA 
 
NA 
 
NA 
 
NA 
 
 
• 
Review medical photos to confirm diagnosis of PSACH. 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review urine pregnancy test to determine eligibility based on inclusion/exclusion criteria. 
• 
Obtain written informed consent from participants which can be scanned/photographed and emailed to 
Maria.E.Serna@uth.tmc.edu. 
• 
Inform participants of eligibility and enrollment into the study. 
• 
Provide participants with specific instructions needed to participate in the study. 
• 
Schedule phone visits for eligible participants for the duration of the study. 
 
Baseline Phone call (Visit 1, Day 0) 
• 
Patient will be contacted after receipt of initial study package via postal mail (including medications and 
information for blood draw to assess kidney function, liver function and blood cell count). The complete 
metabolic panel includes analysis of renal function [blood urea nitrogen (BUN), creatinine], liver function 
[total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate 
aminotransferase (AST)], glucose, electrolytes [calcium, sodium, potassium, carbon dioxide (bicarbonate), 
chloride], protein [albumin, total protein]. The complete blood count (CBC) includes analysis of red blood 
count, hemoglobin, hematocrit, white blood cell count, platelet count. Platelet count below 50,000 per l 
in CBC which indicates increased bleeding risk will result in exclusion. 
• 
For Participants in the United States they will be asked to complete blood draw to the closest LabCorp or 
from their local facility at our cost. For the International participants blood need to be draw from a local 
facility an mailed to us for analysis at the local labcorp lab. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.1.2 
STANDARD OF CARE STUDY  PROCEDURES 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
7.2.2 
OTHER ASSAYS OR  PROCEDURES 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND  STORAGE 
7.2.4 
SPECIMEN SHIPMENT 
7.3 
STUDY SCHEDULE 
7.3.1 
SCREENING/ENROLLMENT (VISIT 0) 
7.3.2 
ENROLLMENT/BASELINE 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
• 
Query participants about any changes in inclusion/exclusion criteria. 
• 
Patients will be asked to start taking study medication on the next day. 
• 
Admininister HRQoL instrument. 
 
 
Follow-up Phone call (Visits  2, 3, 5, 6 and 7: Days 30, 60, 120, 150 and 180 -/+ 5 working days) 
• 
Record adverse events as reported by participant to study co-ordinator. Study coordinator will ask about 
gastrointestinal health, any bleeding events and unusual bruising. PI will follow up with participant to assess 
the adverse events and determine whether to terminate participation. 
• 
Record participant’s adherence to treatment protocol. 
• 
Inquire about any medication and health condition changes. 
• 
Admininister HRQoL instrument. 
• 
Self-reported will be obtained from all study subjects using the Numeric Pain Rating Scale to score the 
subject’s pain on a 0 to 10 scale. This scale has been validated and widely used33-38.  Pain will be 
ascertained daily (including during the “washout” period between the two intervention periods) through a 
daily pain log kept by participants. The pain logs will be requested from participants at each follow-up visit 
and at the end of each month in the treatment periods, and data from the pain logs will be compiled and 
analyzed at the start and end of each of the two treatment periods (on days 0, 90, 120, and 210). 
• 
Request participant to mail back or email their pain log and a photo of the empty bottle at end of the 
month 
• 
Inform participant to start on their next 30 days aliquot of study drug. 
 
Follow-up Visit (Visit 4, Day 90 -/+ 5 working days) 
• 
Inform patient that they are supposed to not take any study medication for the next 30 days but should 
continue their pain logs. 
• 
Record adverse events as reported by participant to study co-ordinator. Study coordinator will ask about 
gastrointestinal health, any bleeding events and unusual bruising. PI will follow up with participant to assess 
the adverse events and determine whether to terminate participation. 
• 
Record participant’s adherence to treatment protocol. 
• 
Inquire about any medication and health condition changes. 
• 
Admininister HRQoL instrument. 
• 
Request participant to mail back or email their pain log and mail back any unused medication or email a 
photo of the empty bottle. The data from the pain logs will be compiled and analyzed at the start and end 
of each two treatment periods (on days 0, 90, 120, and 210). 
• 
Ask participants about which medication, reserveratrol or placebo, they think they were taking during the 
last 90 day period (evaluation of the success of blinding). 
• 
Female participants in the United States will be asked to take a urine pregnanacy test at local labcorp or 
local lab. Email a photo of self administered pregnancy test supplied by us for female international 
participants within 30 days prior to next medication mail out. 
• 
Participants will be asked to complete blood draw to the closest LabCorp or from their local facility at our 
cost. For the International participants omplete blood draw to the closes local facilityblood and mailed to 
us for analysis at local Labcorp lab. 
• 
The complete metabolic panel includes analysis of renal function [blood urea nitrogen (BUN), creatinine], 
liver function [total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate 
aminotransferase (AST)], glucose, electrolytes [calcium, sodium, potassium, carbon dioxide (bicarbonate), 
chloride], protein [albumin, total protein]. The complete blood count (CBC) includes analysis of red blood 
count, hemoglobin, hematocrit, white blood cell count, platelet count. Platelet count below 50,000 per l 
in CBC which indicates increased bleeding risk will result in removal from the study. 
7.3.3 
FOLLOW-UP 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
 
Final Study Visit (Visit 8, Day 210 +/- 5 working days) 
• 
Inform patient that they have completed the study. 
• 
Record adverse events as reported by participant to study co-ordinator. Study coordinator will ask about 
gastrointestinal health, any bleeding events and unusual bruising. PI will follow up with participant to assess 
the adverse events and determine whether to terminate participation. 
• 
Record participant’s adherence to treatment protocol. 
• 
Inquire about any medication and health condition changes. 
• 
Participants will be asked to complete blood draw from their local facility at our cost to assess kidney 
function, liver function and blood cell count. The complete metabolic panel includes analysis of renal 
function [blood urea nitrogen (BUN), creatinine], liver function [total bilirubin, alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), and aspartate  aminotransferase  (AST)],  glucose,  electrolytes  [calcium, 
sodium, potassium, carbon dioxide (bicarbonate), chloride], protein [albumin, total protein]. The complete 
blood count (CBC) includes analysis of red blood count, hemoglobin, hematocrit, white blood cell count, 
platelet count. Platelet count below 50,000 per l in CBC which indicates increased bleeding risk will result 
in removal from the study. 
• 
Admininister HRQoL instrument. 
• 
Request participant to mail back or email their pain log and mail back any unused medication or email a 
photo of the empty bottle. The data from the pain logs will be compiled and analyzed at the start and end 
of the two treatment periods (on days 0, 90, 120, and 210). 
• 
Ask participants about which medication, resveratrol or placebo, they think they were taking during the 
last 90 day period (evaluation of the success of blinding). 
 
Post Study Visit (Visit 9, Day 240 +/- 5 working days) 
• 
Participants will be queried regarding any AE/SAE. 
 
 
If the study terminates early, the participants will be called and notified of study termination. In addition, the call 
will include the following: 
• 
Information will be collected on any adverse events that the subjects may have experienced during their 
participation in the study. If the participant reports any adverse events, especially if they were the reason 
for early termination, the participant will be advised to seek medical assistance from their primary care 
physician. 
• 
Participants will be asked to mail back any unused medication or email a photo of the empty bottle. 
Participants will be asked to mail back or email their pain log. 
• 
HRQoL will be administered. 
• 
Partipants will be informed that they will be re-contacted 30 days post-termination visit to assess any 
AE/SAE. 
 
 
Visit type 
Scree 
n-ing 
Start 
1st 
arm 
Follo 
w-up 
Follo 
w-up 
End 
1st 
arm 
Wash 
out 
perio 
d 
Start 
2nd 
arm 
Follo 
w-up 
 
Follo 
w-up 
End 
of 
study 
Post- 
study 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Day 
0 
30 
60 
90 
120 
150 
180 
210 
240 
7.3.4 
FINAL STUDY VISIT 
7.3.5 
EARLY TERMINATION VISIT 
7.3.7 
SCHEDULE OF EVENTS  TABLE 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
Procedures 
 
Check I/E criteria 
X 
 
Obtain HIPAA clearance 
X 
 
Informed Consent 
X 
 
Obtain medical/medication 
history 
X 
 
Urine pregnancy test 
X 
X 
 
Blood test 
X 
X 
 
X 
HRQoL assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Request pain logs 
X 
X 
X 
X 
X 
X 
X 
Pain assessment (compile and 
analyze pain monthly average 
from pain logs) 
X 
X 
X 
 
X 
Request unused mediction or 
photo of empty bottle 
X 
X 
X 
X 
X 
X 
SE/AE/SAE ascertainment 
X 
X 
X 
X 
X 
X 
X 
X 
Query change in medications 
X 
X 
X 
X 
X 
X 
X 
X 
Query change in health status 
X 
X 
X 
X 
X 
X 
X 
X 
Blinding success evaluation 
x 
 
x 
Asked to start next month’s 
dose 
X 
X 
X 
X 
X 
X 
Asked to stop taking all study 
drugs 
X 
 
X 
 
NA 
 
None 
 
None 
 
Current use of resveratrol at time of study start (Day 0). Use of NSAIDs or aspirin. Blood thinners, lovastatin, 
ketoconazole, itraconazole, fexofenadine and triazolam. Alfentanil, Cyclosporine, Dihydroergotamine, Dofetilide, 
Ergotamine, Fentanyl, Flibanserin, Oxycodone, Pimavanserin, Pimozide, Quinidine, Saquinavir, Sirolimus, 
Tacrolimus, Temsirolimus, Theophylline, Tizanidine, Thioridazine, Fosphenytoin, Phenytoin or Warfarin. 
 
None 
 
The participants pain medications can be taken during the study and the use of pain medication will be recorded to 
determine if resveratrol reduces use of pain medication and/or self reported pain.  Non-NSAID pain relievers  such 
7.4 
JUSTIFICATION FOR SENSITIVE  PROCEDURES 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND  PROCEDURES 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND  PROCEDURES 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND  PROCEDURES 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND  PROCEDURES 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND  PROCEDURES 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
as Tylenol can be used to control pain. If the rescue pain med(s) can’t sufficiently control the pain, then the 
participant will be taken off the study. 
 
Since resveratrol reserveage is an over-the-counter supplement, patients will have full access to product after study 
concludes. 
 
 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator  or 
co-investigator or DSMB, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
. 
 
Unanticipated problems involve risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described 
in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; 
and (b) the characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“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); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
This study will use the Office for Human Research Protections (OHRP) definition of UP. 
 
 
8.2.1 
SEVERITY OF EVENT 
The AE grading system used is based on NIH National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of 
severity for each AE based on this general guideline: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
8.1.1 
DEFINITION OF ADVERSE EVENTS  (AE) 
8.1.3 
DEFINITION OF  UNANTICIPATED PROBLEMS (UP) 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY   CLOSURE 
8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY  PARAMETERS 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS  (SAE) 
8.2 
CLASSIFICATION OF AN ADVERSE  EVENT 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
A Semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a Grade is not available. 
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for 
Grade selection. Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. 
 
Grade of Adverse Event (CTCAE version 5.0) 
Adverse Events 
1 
2 
3 
4 
5 
Kidney Function 
Creatinine 
increased 
>ULN-1.5x 
ULN 
>1.5-3.0x 
baseline; >1.5- 
3.0x ULN 
>3.0 baseline; 
>3.0-6.0x ULN 
>6.0x ULN 
- 
Acute Kidney Injury 
- 
- 
Hospitalization 
indicated 
Life-threatening 
consequences; 
dialysis 
indicated 
Death 
Hyperkalemia (A 
disorder 
characterized by 
laboratory test 
results that indicate 
an elevation in the 
concentration of 
potassium in the 
blood; associated 
with kidney failure 
or sometimes with 
the use of diuretic 
drugs.) 
>ULN-5.5 
mmol/L 
>5.5-6.0 
mmol/L 
>6.0-7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; 
life-threatening 
consequences 
Death 
Liver Function 
Alanine 
aminotransferase 
increased 
>ULN-3.0x 
ULN if baseline 
was normal; 
1.5 - 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0-5.0x ULN 
if baseline was 
normal; >3.0 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0-20.0x ULN if 
baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
- 
Alkaline 
phosphatase 
increased 
>ULN-2.5x 
ULN if baseline 
was normal; 
2.0 - 2.5 x 
baseline if 
baseline was 
abnormal 
>2.5-5.0x ULN 
if baseline was 
normal; >2.5 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0-20.0x ULN if 
baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
- 
Aspartate 
aminotransferase 
increased 
>ULN-3.0x 
ULN if baseline 
was normal; 
1.5 - 3.0 x 
>3.0-5.0x ULN 
if baseline was 
normal; >3.0 - 
5.0 x baseline if 
>5.0-20.0x ULN if 
baseline was 
normal; >5.0 - 
20.0 x baseline if 
>20.0x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
- 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
baseline if 
baseline was 
abnormal 
baseline was 
abnormal 
baseline was 
abnormal 
baseline was 
abnormal 
Blood bilirubin 
increased 
>ULN-1.5x 
ULN if baseline 
was normal; > 
1.0 - 1.5 x 
baseline if 
baseline was 
abnormal 
>1.5-3.0x ULN 
if baseline was 
normal; >1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0-10.0x ULN if 
baseline was 
normal; >3.0 - 
10.0 x baseline if 
baseline was 
abnormal 
>10.0x ULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal 
- 
Gastrointestinal Disorders 
Nausea 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, or 
hospitalization 
indicated 
- 
- 
Diarrhea 
Increase of <4 
Increase of 4 - 
Increase of >=7 
Life-threatening 
Death 
stools per day 
6 stools per 
stools per day 
consequences; 
over baseline; 
day over 
over baseline; 
urgent 
mild increase 
baseline; 
hospitalization 
intervention 
in ostomy 
moderate 
indicated; severe 
indicated 
output 
increase in 
increase in 
compared to 
ostomy output 
ostomy output 
baseline 
compared to 
compared to 
baseline; 
baseline; limiting 
limiting 
self care ADL 
instrumental 
ADL 
Platelet count 
<LLN- 
<75,000 - 
<50,000 - 
<25,000/mm3; 
- 
decreased 
75,000/mm3; 
50,000/mm3; 
25,000/mm3; 
<25.0 x 10e9/L 
<LLN -75.0 x 
<75.0- 50.0 x 
<50.0- 25.0 x 
10e9 /L 
10e9 /L 
10e9 /L 
Anemia 
Hemoglobin 
Hgb <10.0 - 8.0 
Hgb <8.0 g/dL; 
Life-threatening 
Death 
(Hgb) <LLN - 
g/dL; <6.2 -4.9 
<4.9 mmol/L; <80 
consequences; 
10.0 g/dL; 
mmol/L; <100 - 
g/L; transfusion 
urgent 
<LLN - 6.2 
80g/L 
indicated 
intervention 
mmol/L; <LLN  
indicated 
- 100 g/L 
 
 
 
The clinician’s assessment of an AE's relationship to study agent (supplement) is part of the documentation process, 
but it is not a factor in determining what is or is not reported in the study. If there is any doubt as to whether a 
clinical observation is an AE, the event should be reported. All AEs must have their relationship to study agent 
assessed. In a clinical trial, the study product must always be suspect. To help assess, the following guidelines are 
used. 
8.2.2 
RELATIONSHIP TO STUDY  AGENT 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
• 
Related – The AE is known to occur with the study agent, there is a reasonable possibility that the study 
agent caused the AE, or there is a temporal relationship between the study agent and event. Reasonable possibility 
means that there is evidence to suggest a causal relationship between the study agent and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study agent caused the 
event, there is no temporal relationship between the study agent and event onset, or an alternate etiology has been 
established. 
 
The DSMB will be responsible for determining whether an AE is expected or unexpected. An AE will be  considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent. 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study phone interviews  with 
the study participants or upon review by the DSMB. All AEs including local and systemic reactions not meeting the 
criteria for SAEs will be captured on the appropriate case report forms. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study drug (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study will be documented appropriately in the database regardless of relationship. All AEs will be followed 
to adequate resolution. 
Any PSACH-related medical issue present at the time the participant is screened will be considered as baseline and 
not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will 
be recorded as an AE. Unanticipated problems will be recorded in the data collection system throughout the study. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration of 
each episode. 
The study staff will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study 
visit, the study staff will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
 
 
 
The study coordinator will ask about gastrointestinal health any bleeding events and unusual bruising and fill out the 
AE forms as events are noted.  The DSMB will be informed of all AEs. 
 
The study clinician will complete a SAE Form within the following timelines: 
• 
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the 
SAE Form and submitted to the DSMB within 24 hours of site awareness. 
• 
Other SAEs regardless of relationship, will be submitted to the DSMB within 72 hours of site awareness. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or 
the adherence to be stable. Other supporting documentation of the event may be requested by the DSMB and 
should be provided as soon as possible. The PI will be responsible for notifying FDA of any unexpected fatal or life- 
threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the 
sponsor's initial receipt of the information. 
8.2.3 
EXPECTEDNESS 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND    FOLLOW-UP 
8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING 
8.4.2 
SERIOUS ADVERSE EVENT  REPORTING 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
 
None 
 
None 
 
Although resveratrol is likely to not have any untoward effect during pregnancy either to the mother or the   fetus, 
there is no definitive data on the safety of the supplement during pregnancy. Therefore, pregnancy is considered an 
exclusion criteria in this study. During enrollment, female participants will be asked about their intention to get 
pregnant in the next few months. Additionally, female participants of child-bearing age will be asked to practice 
adequate contraception methods known to prevent pregnancy. They will be asked to notify the study team when 
they become pregnant and to stop study medication if such an event occurs. A urine pregnancy test will verify 
potential participants are not pregnant prior to test medication being mailed. A urine pregnancy test will be 
administered for particiapants in United States and Interantional participants will self administer urine preganancy 
test at the end of first 90 day period of placebo or resveratrol or during the 30 day washout period. 
 
 
Administration of study agent will be halted study-wide when any of the following occur and are reported to the 
DSMB: 
• 
three grade 3 AEs 
• 
three grade 1 or grade 2 AEs of the same type 
• 
three grade 1 or grade 2 AEs related to liver function 
• 
one grade 4 or 5 AE 
The research coordinator will notify the principal investigators and co-investigator immediately when the the study 
stopping criteria are met and enrollment screens will stop accepting new study participants. The principal 
investigator will inform the Data and Safety Monitoring Board (DSMB) members within 24 hours of this occurrence 
and will provide the DSMB with AE listing reports. The DSMB will convene an ad hoc meeting by teleconference or 
in writing as soon as possible. The DSMB will provide recommendations for proceeding with the study to the principal 
investigator. The principal investigator will inform the FDA of the temporary halt and the disposition of the study. 
An individual participant will be asked to discontinue study medication if any of the following occur: 
• 
one grade 3, 4, or 5 AE 
• 
three grade 2 AEs 
• 
five grade 1 AEs 
 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate expertise, 
including gastroenterology, infectious diseases and hematology The DSMB will meet at least semiannually to assess 
safety and efficacy data on each arm of the study. The DMSB will operate under the rules of an approved charter 
that will be written and reviewed at the organizational meeting of the DSMB. At this time, each data element that 
the DSMB needs to assess will be clearly defined. The DSMB will provide its input to PI. 
 
 
None 
 
8.4.3 
UNANTICIPATED PROBLEM REPORTING 
8.4.4 
EVENTS OF SPECIAL  INTEREST 
8.4.5 
REPORTING OF PREGNANCY 
8.5 
STUDY HALTING RULES 
8.6 
SAFETY OVERSIGHT 
9 
CLINICAL MONITORING 
10 
STATISTICAL CONSIDERATIONS 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
  10.1     STATISTICAL AND ANALYTICAL PLANS 
 
The primary outcome (change in pain between baseline and monthly pain average score) will be scored using the 
the Numeric Pain Rating Scale. Based on prior studies that utilized these scales, a difference of at least 2 units on the 
11-point scale are considered to be a reflection of a true change in pain39,40. Median and mean monthly pain will be 
compared. The pain score on each day of month one will be averaged to obtain the average pain score for month 
one, and the same will be done for months two and three, and each of the monthly average scores will be compared 
to baseline. For the secondary outcome measure, baseline HRQoL will be compared to the 30, 60, and 90 day HRQoL 
scores. 
Data from the daily pain logs and the monthly HRQoL assessments will be used to evaluate changes in outcomes 
within each intervention period stratified by study drug. The analysis will be performed within the framework of the 
2x2 crossover study design. Baseline charachteristics (demographic and clinical) will be tabulated. Exploratory 
analyses will be performed to assess differences in outcomes as stated above after further stratification by gender. 
 
  10.2     STATISTICAL HYPOTHESES 
 
The primary hypothesis is that patients’ report of pain (and/or use of pain medication) will be 2.8 points lower on 
the pain scale (0-10)  while on the resveratrol than while on placebo. 
The secondary hypothesis for this study states that the change in self-reported HRQoL from the start of the study 
period to the end will be different in PSACH patients during the period they are on resveratrol compared to when 
they are on placebo. 
 
  10.3     ANALYSIS DATASETS 
 
The dataset analyzed will be comprise of demographic and clinical information obtained from the patient, the pain 
scores obtained from the pain and HRQoL instruments described above. The database will be maintained by the 
study coordinator and will be password-protected and stored on the secure and HIPAA-compliant University of Texas 
Health Science Center’s zone 100 network. It will be accessible only to the study staff. 
 
  10.4 
DESCRIPTION OF STATISTICAL  METHODS 
 
 
Multilevel mixed-effects models will be utilized to assess the data while accounting for the lack of independence of 
data obtained from multiple time-points while considering the initial (baseline) outcome scores, type of intervention 
(placebo vs. resveratrol) and the sequence of intervention (placebo first, then resveratrol, or vice versa). This analysis 
wil be performed using STATA (v.14, College Station, TX). Exploratory analyses after stratification by subject’s gender 
will also be performed. 
 
A baseline pain assessment will take place at the first visit (day 0). Pain will then be ascertained daily (including 
during the “washout” period between the two intervention periods) through a daily pain log kept by participants. 
The pain logs will be requested from participants at each follow-up visit and at the end of each month in the 
treatment periods, and data from the pain logs will be compiled and analyzed at the start and end of each of the 
two treatment periods (on days 0, 90, 120, and 210). Each of these scores will then be entered as raw values for each 
subject if the parameter distribution is non-normal, ranked values will be used as units of analysis. 
The primary endpoint will be change in pain score between baseline and monthly average pain score. The pain score 
on each day of month one will averaged to obtain the average pain score for month one, and the same will be done 
10.4.1   GENERAL APPROACH 
10.4.2   ANALYSIS OF THE PRIMARY EFFICACY  ENDPOINT(S) 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
for months two and three, and each of the monthly average scores for resveratrol and placebo periods will be 
compared to baseline. 
In an extreme condition, if a sufficiently large proportion (>30%) of the study subjects experience no pain (a score of 
0), zero-inflated negative binomial models will be utilized to analyze the data while considering the individuals that 
report no pain. 
 
The data from the HRQoL instruments will be ascertained for each subject at the following time-points – prior to the 
start of the first period (first intervention), at 30 days after the start of the first period, at 60 days after the start of 
the first period, and at the end of the first period (90 days), at the start of the second period (second intervention) 
after the “washout” time of 30 days has passed, at 30 days after the start of the second period, at 60 days after the 
start of the second period, and finally at the end of the second period. These normalized scores will then be used in 
generalized mixed models as stated above. Baseline HRQoL will be compared to the 30, 60, 90 day HRQoL scores. 
 
The study DSMB will meet after every 10 patients have successfully completed the full study and all study data has 
been completed. The DSMB will be presented with all study-duration events (signs/symptioms/co-morbidities) that 
have been ascertained from all the patients that have completed their participation in the study and will be classified 
as study-related vs. incidental. The crude rate of the study-related event(s) will be tabulated with one-sided 95% 
confidence intervals41. Additionally, for study-related events that occur in more than 5 patients will be be further 
analyzed to incorporate duration of exposure to study drug. 
 
At the end of each intervention period, subjects will be asked to complete two questions on adherence.     The first 
question will incorporate a visual analog scale (VAS) as a means to calculate self-reported adherence to study 
medication use. The second question will inquire about reasons for their non-compliance if any. These scales will be 
assessed after successful completion of every 10 patients so that any issues with adherence may be identified early 
and rectified for subsequent study participants. 
 
Baseline descriptive statistics will be presented for demographic and clinical information for each patient. These will 
be tabulated and described as frequencies and percentages (for categorical data) and mean and standard deviations 
or median and inter-quartile ranges (for normally distributed and non-normally distrubted continuous data, 
respectively). No statistical comparisons will be performed between the two as this is a randomized clinical trial. 
 
None 
 
The study DSMB will meet after every 10 patients have successfully completed the full study and all study data has 
been completed. Nonblinded information on all study-duration events (signs/symptioms/co-morbidities) that have 
been ascertained from all the patients will be classified as study-related vs. incidental. 
 
10.4.3   ANALYSIS OF THE SECONDARY  ENDPOINT(S) 
10.4.4   SAFETY ANALYSES 
10.4.5   ADHERENCE AND RETENTION ANALYSES 
10.4.6   BASELINE DESCRIPTIVE STATISTICS 
10.4.7   PLANNED INTERIM ANALYSES 
10.4.7.1 
SAFETY REVIEW 
10.4.7.2 
EFFICACY REVIEW 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
There will be no interim analysis to assess efficacy performed for this study as this is a rare condition and there are 
a finite number of patients available for recruitment into the study. Adjusting the Type I error rate and recruiting 
additional patients is not achieveable. However, safety assessments will be ongoing by the DSMB as described in 
section 8.6 
 
None 
 
The design incorporates repeated measurements. The statistical models will account for that. 
 
Tabulation of indidivual response data for regulatory bodies will be provided as needed.        The data included per 
patient will be dependent on the study report being presented. If needed all repeated measurements from every 
study subject will be presented in the appropriate tables. 
 
None 
 
  10.5     SAMPLE SIZE 
 
Although studies haven’t quantified pain variability in PSACH, other studies have utilized a pain VAS and have 
reported standard deviation (SD) of the difference between scores for the same patient of about 10-15 on a 1-100 
scale. In addition, previous research by one of the investigators has suggested that a strong placebo effect can be 
present in studies using the pain VAS at a magnitude of about 20 on a 1-100 scale. Assuming a similar degree of 
variability in our study population and considering the placebo effect as reported, with a sample size of 30 
participants at a Type I error rate of 5%, the minimal detectable difference would be 2.8 units at a SD of 10 and 
power of 80%, 4.25 at a SD of 15 and power of 80%, 3.3 at a SD of 10 and power of 90%, and 4.9 at a SD of 15 and 
power of 90%. Considering that there are about 300 potential patients that can be approached through the “Little 
People of America” support group and the Facebook PSACH group, we should be able to recruit into the study at 
least half of those highly motivated and invested individuals. We should be able to achieve our sample size of 30 
patients for this study, even assuming a considerably high 33% attrition rate. We will screen 60 to enroll 30. 
 
  10.6 
MEASURES TO MINIMIZE  BIAS 
 
 
One hundred individuals with PSACH will enrolled in the study and then randomized to receiving resveratrol or 
placebo first based on randomization assignment by biostatistician. We will not replace enrollees that drop out as 
we have statistical power to lose 10% of the cohort ad still determine whether the supplement provides relief of 
pain. All study participants will be blinded to the study drug. All study investigators and analysts will be blinded to 
the study drug with the exception of the study coordinator who will be responsible for mailing out the study 
medications. 
 
10.4.8   ADDITIONAL SUB-GROUP ANALYSES 
10.4.9   MULTIPLE COMPARISON/MULTIPLICITY 
10.4.10  TABULATION OF INDIVIDUAL RESPONSE DATA 
10.4.11 EXPLORATORY ANALYSES 
10.6.1   ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
10.6.2  EVALUATION OF SUCCESS OF   BLINDING 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
At the end of each study period, all study subjects will be asked to respond to a single question asking them to 
identify if they were on the study drug or placebo during the previous intervention period. This data will be analyzed 
after 20, 40 and all subjects have completed the study to evaluate the success of blinding. 
 
The study blind/participant code will be broken only in the case of an AE or SAE if the DSMB deems it important for 
appropriate assessment of the event. In this scenario, the study coordinator will communicate with the DSMB 
regarding the randomization arm of the particular participant. Other study team members will remain blinded. 
 
All study documents and data will be kept securely by the study coordinator.  All electronic data will be  password- 
protected and stored on HIPAA compliant NAS servers at the McGovern Medical School University of Texas Health 
Science Center at Houston. All hard-copies of the ICFs, CRFs, consent forms, pain logs, HRQoL assessments and other 
data collected from patients will be stored in a locked filing cabinet on the premises of the McGovern Medical School 
at the University of Texas Health Science Center at Houston. Access to all these records will be limited to the study 
coordinator. The coordinator will tabulate and aggregate information for consumption by the DSMB, study team and 
IRB if applicable. 
 
Quality control procedures will be implemented by the study-coordinator to monitor all study documentation for 
completeness and accuracy. Any missing data or data anomalies will be communicated to the principal investigator 
for clarification/resolution. 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing, and inspection by any local and regulatory authorities. 
 
 
  13.1 
ETHICAL STANDARD 
 
The investigators will ensure that this study is conducted in full conformity with Regulations for the Protection of 
Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6.] 
 
  13.2 
INSTITUTIONAL REVIEW BOARD 
 
Committee for the Protection of Human Subjects 
University of Texas Health Science Center at Houston 6410 Fannin, Suite 1100, Houston, Texas 77030; Phone 713- 
500-7943; Fax 713-500-7951, Email cphs@uth.tmc.edu 
 
  13.3 
INFORMED CONSENT PROCESS 
 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant and 
written documentation of informed consent is required prior to ascertaining diagnostic information and/or starting 
intervention/administering study product. The following consent materials are submitted with this protocol : 1) adult 
consent form. 
 
10.6.3   BREAKING THE STUDY BLIND/PARTICIPANT  CODE 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE   DATA/DOCUMENTS 
12 
QUALITY ASSURANCE AND QUALITY  CONTROL 
13 
ETHICS/PROTECTION OF  HUMAN SUBJECTS 
13.3.1   CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO   PARTICIPANTS 
13.3.2  CONSENT PROCEDURES AND  DOCUMENTATION 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
Study participants and/or their family members will be informed of risks and possible benefits of participation in this 
study. Consent forms will be IRB-approved and the participant will be asked to read and review the document. The 
investigator/study corrdinator will explain the research study to the participant and answer any questions that may 
arise. All participants must be able to communicate in English and they will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent form, discuss 
with other family members and ask questions prior to signing. The participant will sign the informed consent 
document prior to any participation in the study and mail the consent form to the study coordinator in a provided 
self-addressed stamped envelope or scan/photograph and email to study coordinator. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent document will be 
given to the participants for their records or if the participant has they original they will retain this copy for their 
records. The rights and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
  13.4     PARTICIPANT AND DATA CONFIDENTIALITY 
 
The study protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the principal investigator. 
Representatives of the IRB may inspect all documents and records required to be maintained by the principal 
investigator, for the participants in this study. The clinical study site will permit access to all records. 
The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for 10 years. 
 
No human samples or specimens will be collected during this study 
Data collected will be analyzed to determine if resveratrol has any benefit for pain in PSACH. 
Storage: Access to stored data will be limited using password electronic protection and locked file cabinets. Data will 
be stored using codes assigned by the investigators. Data will be kept in password-protected computers. Only 
investigators will have access to the samples and data. 
 
  13.5 
FUTURE USE OF  STORED SPECIMENS 
 
N/A. 
 
 
 
  14.1 
DATA COLLECTION AND MANAGEMENT  RESPONSIBILITIES 
 
Pain logs will be mailed or emailed to the the study coordinator. The study coordinator will also be responsible for 
the data collection and storage of the documents in a secured location. 
 
  14.2 
STUDY RECORDS RETENTION 
 
All study documentation will be kept in a secure location for 10 years and then destroyed. 
 
  14.3     PROTOCOL DEVIATIONS 
 
As a result of any protocol deviation, corrective actions will be developed by the PI and implemented promptly. The 
study IRB will be notified of any protocol deviation within 10 working days of the deviation. The deviations will also 
be logged in a “Protocol Deviation Log” which will be part of the study quality monitoring plan. 
13.4.1   RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR   DATA 
14 
DATA HANDLING AND RECORD  KEEPING 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
  14.4 
PUBLICATION AND DATA SHARING  POLICY 
 
This study is not funded. We will submit a manuscript with the findings to a peer-reviewed journal. In addition, the 
clinical trial be registered with clinicaltrials.gov. 
 
 
  15.1     STUDY LEADERSHIP 
 
The Steering Committee, composed of Drs. Hecht and Posey, who are the PIs, will govern the conduct of the study. 
The Steering Committee meets on a weekly basis. Study progress, including recruitment rates protocol deviations, 
quality monitoring and DSMB reports will be assessed by the Steering Committee on an annual basis. 
 
This project is independent of any actual or perceived influence, such from the pharmaceutical industry.      We are 
using an over the counter supplement that is purchased and there is no financial contribution from the 
manufacturer. 
 
 
1. Posey KL, Coustry F, Veerisetty AC, Hossain M, Alcorn JL, Hecht JT. Antioxidant and anti-inflammatory agents 
mitigate pathology in a mouse model of pseudoachondroplasia. Human molecular genetics. 2015. doi: 
10.1093/hmg/ddv122. PubMed PMID: 25859006. 
2. Mobasheri A, Henrotin Y, Biesalski HK, Shakibaei M. Scientific evidence and rationale for the development of 
curcumin and resveratrol as nutraceutricals for joint health. Int J Mol Sci. 2012;13(4):4202-32. doi: 
10.3390/ijms13044202. PubMed PMID: 22605974; PMCID: PMC3344210. 
3. Csaki C, Keshishzadeh N, Fischer K, Shakibaei M. Regulation of inflammation signalling by resveratrol in human 
chondrocytes in vitro. Biochem Pharmacol. 2008;75(3):677-87. PubMed PMID: 17959154. 
4. Dave M, Attur M, Palmer G, Al-Mussawir HE, Kennish L, Patel J, Abramson SB. The antioxidant resveratrol 
protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production. Arthritis 
Rheum. 2008;58(9):2786-97. PubMed PMID: 18759268. 
5. Elmali N, Baysal O, Harma A, Esenkaya I, Mizrak B. Effects of resveratrol in inflammatory arthritis. 
Inflammation. 2007;30(1-2):1-6. PubMed PMID: 17115116. 
6. Elmali N, Esenkaya I, Harma A, Ertem K, Turkoz Y, Mizrak B. Effect of resveratrol in experimental osteoarthritis 
in rabbits. Inflamm Res. 2005;54(4):158-62. PubMed PMID: 15883738. 
7. Liu FC, Hung LF, Wu WL, Chang DM, Huang CY, Lai JH, Ho LJ. Chondroprotective effects and mechanisms of 
resveratrol in advanced glycation end products-stimulated chondrocytes. Arthritis Res Ther. 2010;12(5):R167. 
PubMed PMID: 20825639. 
8. Shakibaei M, Mobasheri A, Buhrmann C. Curcumin synergizes with resveratrol to stimulate the MAPK signaling 
pathway in human articular chondrocytes in vitro. Genes Nutr. 2011;6(2):171-9. PubMed PMID: 21484156. 
9. Wang J, Gao JS, Chen JW, Li F, Tian J. Effect of resveratrol on cartilage protection and apoptosis inhibition in 
experimental osteoarthritis of rabbit. Rheumatol Int. 2010. PubMed PMID: 21327438. 
10. Yiu EM, Tai G, Peverill RE, Lee KJ, Croft KD, Mori TA, Scheiber-Mojdehkar B, Sturm B, Praschberger M, Vogel 
AP, Rance G, Stephenson SE, Sarsero JP, Stockley C, Lee CY, Churchyard A, Evans-Galea MV, Ryan MM, Lockhart PJ, 
Corben LA, Delatycki MB. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose 
resveratrol, without effect on frataxin levels. J Neurol. 2015;262(5):1344-53. Epub 2015/04/08. doi: 
10.1007/s00415-015-7719-2. PubMed PMID: 25845763. 
15 
STUDY ADMINISTRATION 
16 
CONFLICT OF  INTEREST POLICY 
17 
LITERATURE REFERENCES 


IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
11. Voduc N, la Porte C, Tessier C, Mallick R, Cameron DW. Effect of resveratrol on exercise capacity: a 
randomized placebo-controlled crossover pilot study. Appl Physiol Nutr Metab. 2014;39(10):1183-7. Epub 
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IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
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IRB NUMBER: HSC-MS-17-0573 
IRB APPROVAL DATE: 05/15/2020 
NIH-FDA Clinical Trial Protocol Template – v1.4 20200401 
Resveratrol Trial for Relief of Pain in Pseudoachondroplasia 
Protocol : HSC-MS-17-0573 
Version 1.4 
04/01/2020 
 
 
 
  APPENDIX 
 
 
Version 
Date 
Significant Revisions