Treatment of Established Chemotherapy-Induced Neuropathy With N-Palmitoylethanolamide, a Cannabimimetic Nutraceutical: A Randomized Double-Blind Phase II Pilot Trial
Phase: PHASE2
Conditions: Chemotherapy-Induced Peripheral Neuropathy, Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
Sponsor: Academic and Community Cancer Research United

ACCRU-SC-2102 
 
1 
 
Academic and Community Cancer Research United (ACCRU) 
 
Treatment of Established Chemotherapy-Induced Neuropathy with N-Palmitoylethanolamide, a 
Cannabimimetic Nutraceutical: A Randomized Double-Blind Phase II Pilot Trial 
For any communications regarding this protocol, please contact the person indicated on the 
Protocol Resource page. This is a stand-alone document found on the ACCRU web site 
(
).  
 
Study Chairs 
 
ACCRU: 
 
  
 
 
  
 
FDA IND  
Sponsor/Investigator:  
 
 
 
 
  
 
 
Study Co-chairs: 
 
 
 
 
 
 
 
          
 
 Statistician:    
  
 
 
  
 
 
  
 
 
 
Drug Availability 
Drug Company Supplied: OptiPEA® (NSC # 760371) – IND# 155458 or Placebo 
 
 Study contributor(s) not responsible for patient care. 
* Grant holder 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
 
Document History 
 
(effective date) 
     Version 1 
 
 03/01/2021 
 
 
 
 
  Version 2 
 
           11/10/2021 
 
 
 
 
  Version 3 
 
           12/20/2021 
  Version 4 
 
          02/16/2022 
Amendment 5  
 
08/03/2023 
 

ACCRU-SC-2102 
 
2 
 
 
Table of Contents 
Section 
Page 
SCHEMA 
4 
1.0 
BACKGROUND ............................................................................................................................. 5 
1.1 
Cannabis and Neuropathic pain .................................................................................................... 5 
1.2 
Rationale for study and introduction to PEA ................................................................................ 5 
1.3 
PEA utility for human pain ........................................................................................................... 6 
1.4 
Animal Models of PEA Regarding CIPN ..................................................................................... 6 
1.5 
PEA Utility for Human CIPN ....................................................................................................... 6 
1.6 
Should the Current Trial Explore CIPN Prevention vs the Treatment of Established CIPN? ...... 7 
1.7 
Palmitoylethanolamide Pharmacology Efficacy and Safety ......................................................... 7 
1.8 
CIPN endpoint measurement tools ............................................................................................. 12 
1.9 
Toxicity and QOL Endpoint Measurement Tools ....................................................................... 12 
2.0 
GOALS 12 
2.1 
Primary ........................................................................................................................................ 12 
2.2 
Secondary .................................................................................................................................... 13 
2.3 
Exploratory ................................................................................................................................. 13 
3.0 
PATIENT ELIGIBILITY ............................................................................................................ 13 
3.1 
Registration -- Inclusion Criteria ................................................................................................ 13 
3.2 
Registration – Exclusion Criteria ................................................................................................ 14 
4.0 
TEST SCHEDULE ....................................................................................................................... 16 
4.1 
Survival Follow-up ..................................................................................................................... 17 
6.0 
REGISTRATION/RANDOMIZATION PROCEDURES ........................................................ 18 
6.1 
Site Procedures ............................................................................................................................ 18 
6.2 
Registration Procedures .............................................................................................................. 18 
6.3 
Randomization Procedures ......................................................................................................... 19 
6.4 
Procedures for Double-Blinding the Treatment Assignment ...................................................... 20 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 20 
7.1 
Palmitoylethanolamide (PEA)/Placebo ....................................................................................... 21 
7.2 
Submission of Patient Completed Measures (Booklets) ............................................................. 21 
7.3 
Unblinding Procedures ................................................................................................................ 22 
8.0 
DOSE AND TREATMENT MODIFICATIONS ....................................................................... 22 
8.1 
Dose Modifications ..................................................................................................................... 22 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE ............................................................... 23 
9.1 
Prohibited Concomitant Medications/Therapy ........................................................................... 23 
10.0 
ADVERSE EVENT (AE) REPORTING AND MONITORING .............................................. 23 
10.1 
Adverse Event Characteristics .................................................................................................... 24 
10.2  Expected vs. Unexpected Events ................................................................................................ 25 
10.3 
Assessment of Attribution ........................................................................................................... 25 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents .................................. 27 
10.5 
Other Required Reporting ........................................................................................................... 29 
11.0 
TREATMENT EVALUATION/MEASURES............................................................................ 30 
11.1 
CIPN endpoint measurement tools ............................................................................................. 30 
11.2 
Toxicity and QOL Endpoint Measurement Tools ....................................................................... 31 

ACCRU-SC-2102 
 
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11.3 
Nurse, clinician, or study assistant Telephone Contact (Appendix VIII) ................................... 31 
12.0 
DESCRIPTIVE FACTORS ......................................................................................................... 31 
13.0 
TREATMENT/FOLLOW-UP DECISION AT EVALUATION OF PATIENT ..................... 31 
13.1 
Treatment Duration/Off protocol treatment ................................................................................ 31 
13.2 
Extraordinary Medical Circumstances ........................................................................................ 31 
13.3 
Ineligible ..................................................................................................................................... 31 
13.4 
Major Violation ........................................................................................................................... 32 
13.5 
Cancel ......................................................................................................................................... 32 
14.0  BODY FLUID BIOSPECIMENS ................................................................................................ 32 
15.0 
DRUG INFORMATION .............................................................................................................. 32 
15.1 
Palmitoylethanolamide (OptiPEA®) .......................................................................................... 32 
15.2 
Placebo ........................................................................................................................................ 34 
16.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 34 
16.1 
Statistical Design ........................................................................................................................ 34 
16.2 
Sample size, Accrual time and Study Duration .......................................................................... 34 
16.3 
Primary Endpoint Analysis Plan ................................................................................................. 35 
16.4 
Secondary/Exploratory Analysis Plans ....................................................................................... 35 
16.5 
Missing Data ............................................................................................................................... 36 
16.6 
Study Monitoring ........................................................................................................................ 37 
16.7 
Study Reporting .......................................................................................................................... 37 
16.8 
Inclusion of Women and Minorities ........................................................................................... 38 
17.0 
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS .......................................... 39 
18.0 
RECORDS AND DATA COLLECTION PROCEDURES ....................................................... 39 
18.1 
Submission Timetable ................................................................................................................. 39 
18.2 
Survival Follow-up ..................................................................................................................... 39 
18.3 
CRF completion .......................................................................................................................... 39 
18.4 
Site responsibilities ..................................................................................................................... 39 
18.5 
Supporting documentation .......................................................................................................... 39 
18.6 
Labeling of materials .................................................................................................................. 39 
18.7 
Overdue lists ............................................................................................................................... 39 
19.0 
BUDGET ........................................................................................................................................ 40 
20.0 
REFERENCES .............................................................................................................................. 41 
APPENDIX I: ACCRU-SC-2102 PATIENT INFORMATION SHEET ............................................. 47 
APPENDIX II: EORTC QLQ-CIPN20 INSTRUMENT ...................................................................... 49 
APPENDIX III: PATIENT GLOBAL IMPRESSION OF CHANGE ................................................. 51 
APPENDIX IV: CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY ASSESSMENT 
TOOL (QUANTITATIVE ITEMS) ........................................................................................................ 52 
APPENDIX V: SYMPTOM EXPERIENCE DIARY –BASELINE ONLY ........................................ 53 
SYMPTOM EXPERIENCE DIARY –DURING TREATMENT ......................................................... 54 
APPENDIX VI: PERIPHERAL NEUROPATHY QUESTION ........................................................... 55 
APPENDIX VII: COGNITIVE FUNCTIONING ASSESSMENT ...................................................... 56 
APPENDIX VIII NURSE/CRP WEEKLY PHONE CONTACT GUIDE .......................................... 57 
APPENDIX IX:  NURSE/STUDY ASSISTANT PHONE CALL AT MONTHS 6 AND 12. ............. 58 
 
 

ACCRU-SC-2102 
 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment for a maximum of 8 weeks or unacceptable adverse events. 
*Survival follow-up, every 6 months until 1 year after registration. 
 
 
**Generic name: N-Palmitoylethanolamide  
  
Brand name(s): OptiPEA® 
  
Availability: McKesson 
 
 
Registration/Randomization 
2:2:1:1 
PEA** 400 mg daily 
(One capsule daily) 
PEA** 800 mg daily 
(One capsule twice 
daily) 
One placebo capsule 
daily 
One placebo capsule 
twice daily 
Survival Follow-up* 

ACCRU-SC-2102 
 
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1.0 
Background 
Chemotherapy-induced peripheral neuropathy (CIPN) is a major and growing problem as cancer 
survivor- ship grows and patients are living longer with advanced cancer[1-3].This topic has been 
identified as being of high priority by NCI’s Symptom Management/Quality of Life Steering 
Committee.    Chemotherapy agents, such as oxaliplatin and paclitaxel, cause long-term toxicity 
for many patients, which can last for years without reprieve and reduce function and quality of 
life.  Resultant chronic pain leads to psychological distress and depression [4].  There are no 
pharmacological agents that are proven to be efficacious in preventing or limiting the 
neurotoxicity to chemotherapy.  Only duloxetine has been found to have modest benefits in 
reducing CIPN [5], while gabapentin, pregabalin and tricyclic antidepressants are relatively 
ineffective [1]. 
1.1 
Cannabis and Neuropathic pain 
Cannabis has moderate quality evidence for moderate relief of neuropathic pain [6]. 
Analgesic mechanisms of cannabis involve inhibition of active neurotransmitter release 
and neuropeptides from presynaptic nerve endings, postsynaptic modulation of neuron 
excitability, activation of descending inhibitory pain pathways, and reduction of neural 
inflammation[7]. Cannabidiol (CBD) produces analgesia through the vanilloid receptor 
TRPV1 activation, reduces anxiety associated with pain through serotonin 5-HT1A 
receptor activation, and rescues 5-HT (serotonin) neurotransmission impaired under 
neuropathic pain conditions [8]. Cannabis also influences brain connectivity altered by 
pain, which can lead to analgesia. The anterior cingulate cortex and dorsal lateral 
prefrontal cortex are 2 major cognitive-emotional pain modulating areas influenced by 
cannabis, and their connections to somatosensory areas are important to the experience of 
pain. These two sites are functionally involved in the analgesic effect of 
(tetrahydrocannabinol) THC [9]. 
A systematic review and meta-analysis of cannabis focused on neuropathic pain relief 
reported that cannabis-based medicine increased the number of people achieving 50% or 
greater pain relief compared with placebo (21% versus 17%); the risk difference (RD) for 
benefit was 0.05 (95% confidence interval (CI) 0.00 to 0.09).  The number needed to treat 
to benefit (NNTB) a single individual was 20 (95% CI 11 to 100). The evidence for 
improvement in Patient Global Impression of Change (PGIC) with cannabis was felt to 
be of very low quality [10].  
The National Institute for health and Care Excellence (NICE) guidelines recommend 
against using commercial phytocannabinoids products for chronic pain. The committee 
found evidence that showed that “CBD reduced chronic pain, but the treatment effect was 
modest (an average improvement of about 0.4 on a scale ranging from 0 to 10)”. 
Cannabis utility is limited by side effects and dose tolerance; classical phytocannabinoids 
have a narrow therapeutic margin.  Having stated this, there may be specific cannabis 
products that, eventually, will be shown to be beneficial and well tolerated. 
1.2 
Rationale for study and introduction to PEA 
N- palmitoylethanolamide (PEA) differs from cannabis since it is an endogenous 
cannabimimetic nutraceutical, a saturated fatty acid which does not directly target 
classical cannabinoid receptors (CB1 and CB2) but significantly reduces pain. PEA has 
been found to have no serious side effects and appears to have a greater therapeutic 
margin, compared to phytocannabinoids [11-15]. PEA analgesic targets include 
peroxisome proliferator-activated receptors (PPAR), vanilloid receptors, and the orphan 
receptor GPR-55. PEA impairs mast cell degranulation and blunts neuropathic pain-

ACCRU-SC-2102 
 
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causing neuroinflammation [16-25]. PEA competitively inhibits fatty acid amide 
hydrolase thus increasing anandamide, which activates CB1 receptors [26]. Another 
entourage effect is the activation and down-regulation of TRPV1 when PEA and 
anandamide bind to TRPV1 [27-30]. PEA also increases spinal serotonin levels, which 
has been shown to reduce neuropathic pain [31, 32]. 
1.3 
PEA utility for human pain 
PEA has been studied in prospective randomized studies involving patients with multiple 
pain phenotypes, including CIPN pain. In one meta-analysis, involving 1289 patients in 
eight trials which included an inactive control group, there was a significantly greater 
pain reduction with PEA compared to inactive control conditions (WMD = 2.03, 95% CI: 
1.19 - 2.87, z = 4.75, P < 0.001) [33]. In a second meta-analysis involving 1,484 patients 
in twelve studies of which three were double-blind trials comparing active comparators 
vs placebo, two open-label trials vs standard therapies, and seven open-label trials 
without comparators, PEA elicited a progressive reduction of pain intensity, significantly 
greater than was seen in control arms. The magnitude of reduction with PEA was 1.04 
points (on a 10-point scale) every two weeks with a 35% response variance explained in 
the linear model. The control group pain reduction intensity was 0.20 points every two 
weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier 
estimator showed a pain score < 3 out of 10 in 81% of PEA treated patients compared to 
only 40.9% in control patients at 60 days of treatment [15].  
1.4 
Animal Models of PEA Regarding CIPN 
There are several studies which have used PEA in animal models of CIPN. PPAR 
activation reduces oxaliplatin neurotoxicity in a rat model [34].  In the same model, a 
single dose of PEA (30mg/kg IP) reduced oxaliplatin pain and, when administered at the 
beginning of oxaliplatin, prevented the lowering of pain thresholds associated with 
oxaliplatin. PEA normalized the electrophysiological activity of spinal nociceptive 
neurons.  Importantly, it did not impair the oxaliplatin-induced human colon cancer 
cytotoxicity (HT-29) [35]. 
In a paclitaxel-induced CIPN model, mice received PEA (9.2mg/kg) which significantly 
reduced allodynia caused by paclitaxel.  The PPAR-alpha antagonist GW6471 reversed 
the anti-nociception of PEA in this model.  PEA with gabapentin (67.4mg/kg) 
synergistically reduced neuropathic pain in this mouse model.  The analgesic actions 
appeared to occur at multiple sites along the peripheral and central nervous system.  
Analgesic tolerance was not observed [36]. 
1.5 
PEA Utility for Human CIPN 
There are multiple human published studies of PEA for various pain phenotypes. What 
has been noted was analgesia with very little to no toxicity observed [12, 13, 33, 37-44]. 
A pilot study, involving 20 patients with CIPN from thalidomide and bortezomib were 
treated with PEA 300mg twice daily which resulted in improved subjective pain and 
neurophysiological parameters after two months of therapy. PEA was very well tolerated 
in this population and reduced pain from 4.5 to 3.4 on the Douleur Neuropathique en 4 
(DN4) questionnaire. EMG sensory action potentials from sural and ulnar nerves and 
motor action potentials from ulnar and peroneal nerves improved, indicating objective 
recovery of myelinated nerve function and conduction which was associated with 
subjective improvement in pain [45]. 

ACCRU-SC-2102 
 
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1.5.1 
Tolerability of PEA 
In the experience of 1590 treated patients, there were no ‘very common’ or 
‘common’ adverse drug reactions (ADRs) being found with PEA following <49 
days treatment times, however there are insufficient data to give information in 
the ‘uncommon’ or ‘rare’ categories [12].  ADRs occurring this early on in 
treatment would likely to have been seen for an incidence of 1/200 or greater.  In 
randomized trials, there were no differences in ADR compared to placebo [46]. 
The number needed to benefit from PEA for sciatic pain to reach 50% pain 
reduction appears to be 1.5 and the number needed to harm is in the hundreds, 
but for the time being not calculable due to the absence of serious and 
troublesome side effects leading to dropouts in clinical trials [39]. 
1.6 
Should the Current Trial Explore CIPN Prevention vs the Treatment of Established 
CIPN?  
As noted above, the animal data show marked benefit in both the prevention of 
neuropathic pain from PEA and also in the treatment of established neuropathic pain. The 
current protocol is designed to look at the treatment of established CIPN issue.  In part, 
this is because we do not know if the reason this product looks good in animal model 
prevention trials is because the analgesic effect of this drug is masking neuropathic 
damage from chemotherapy versus whether it is actually preventing the neuropathic 
damage from happening.  If the former is true, then it may be that we would be causing 
more neuropathic damage but not know about it until later on in the clinical course. 
1.6.1 
What dose(s) of PEA should we study? 
Given that this is a pilot trial, we decided to explore the use of two different 
doses of PEA.  In a variety of human pain trials, PEA doses have ranged from 
300 mg to 1200 mg per day [11].  We opted to study 400 mg/day and 800 
mg/day, as these represent the lower and higher ranges of studied doses and one 
reasonably sized capsule can only contain 400 mg of PEA. A dose response 
relationship has not been established with PEA. Therefore, it is rationale to 
explore two dose levels in this pilot trial to explore this issue. 
1.6.2 
Should we measure the effect of PEA on cognitive function? 
Some studies have reported an association between higher levels of neuro-
inflammation and lower general cognitive function in cancer survivors [47].  
Since PEA, in Alzheimer’s disease patients, has shown promise regarding an 
improvement of cognitive dysfunction [48-50], we will explore whether it has 
any suggestion of improving cognitive function in patients with a history of 
cancer.   
1.7 
Palmitoylethanolamide Pharmacology Efficacy and Safety 
1.7.1 
Pharmacology 
N-(2-acylethanolamine)-exadecanamide, commonly called 
palmitoylethanolamide (PEA), and is a prominent member of the n-
acylethanolamine (NAE) family. It is an Autacoid Local Injury Antagonist amide 
(ALIAmide); ALIAmides are endogenous bioactive ethanolamides with anti-
inflammatory properties.[51, 52] These compounds are produced as a reaction to 
injury and are generated and metabolized in the same cells and tissue that 
developed the injury. The Nobel Prize winner Rita Levi Montalcini first 
described the accumulation of NAE under pathologic and degenerative 

ACCRU-SC-2102 
 
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conditions, resulting in down-modulation of cellular inflammation and mast cell 
activation.[24, 53, 54] The down-modulation of inflammation, 
neuroinflammation and mast cell activation has been found to be associated with 
antinociception in animals and analgesia in clinical studies.[15, 55] 
1.7.2 
Pharmacodynamics 
The pharmacodynamics of PEA, protean as related to analgesia, are : 1.  Down 
modulation of mast cell responses to tissue injury, 2. Activation of peroxisome 
proliferator activated receptor-alpha, 3.  Activation and desensitization of the 
vanilloid receptor, TRPV1, 4. An entourage effect with anandamide through 
competition with fatty acid amide hydrolase catabolism resulting in indirect 
activation of the cannabinoid receptors CB1 and CB2 by increasing anandamide, 
and 5. Inhibition of microglia activation within the central nervous system.[29, 
56-63] 
1.7.3 
Pharmacokinetics  
There are advantages to using ALIAmides over traditional analgesics in that 
ALIAmides influence metabolic pathways within tissues rather than targeting a 
single receptor. Since ALIAmides have no toxic metabolites and do not interact 
with mixed function oxidases or conjugases, they do not have drug-drug 
interactions.  Traditional analgesics, on the other hand, alter physiologic 
processes and cause” collateral” damage through toxic metabolites or off-target 
effects, as seen with opioid analgesics.[38, 64] 
Micronization of PEA, a highly lipophilic compound, to less than 10 microns 
increases both bioavailability and efficacy.[65-67] Almost all trials published in 
the literature have used micronized PEA. 
There are barriers to achieving accurate estimates of PEA pharmacokinetics. 
PEA is normally found in blood and tissue; levels may change with diseases and 
vary independent of oral pharmacokinetics. Levels can be expressions of second 
and third order pathways or local and circulating levels may be influenced by the 
presence of competing endocannabinoids for fatty acid amide hydrolase and the 
expression of enzymes responsible for PEA production.[28, 42, 59, 68]. There 
are few human pharmacokinetic studies. Fortunately, though, there are a sizable 
number of animal studies which used radiolabeled micronized PEA in oral and 
parenteral forms which has provided useful information about PEA 
bioavailability and distribution after administration.[65] 
Concentrations of PEA in tissues are generally higher than in plasma.  
Circulating levels markedly vary during the day.[65] Concentrations in tissues 
and plasma change with injury, particularly with inflammation and in disease 
processes associated with neurodegeneration.[69-74] In the pig brain, PEA levels 
far exceed those of anandamide ( 205 ng / gram versus 6 ng / gram brain 
tissue).[75] 
Human intestinal Caco-2 cell lines are widely used in vitro to estimate drug 
bioavailability. By this method, micronized PEA absorption starts at 30 minutes 
and approximately 20-30% of PEA is projected to be bioavailable. Maximum 
absorption by this method was observed at 3 hours.[29, 65] in a small study of 10 
healthy individuals, 300 mg of micronized PEA produced peak concentrations at 
2 hours; there was a 2-fold increase in circulating PEA levels over baseline.  A 

ACCRU-SC-2102 
 
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second peak was noted later, which was assumed to be due to enterohepatic 
recirculation.[42] 
Animal studies used both parenteral and oral radiolabeled micronized PEA to 
determine oral bioavailability, plasma and tissue levels. Oral micronized PEA in 
corn oil in rats, at a dose of 100 mg/kg, produced plasma levels within 15 
minutes with levels that were 20-fold higher in concentration, relative to 
baseline.  Plasma levels returned to baseline at approximately 2 hours.[76] 
Beagle dogs given 30mg/kg of micronized PEA had a 6-fold increase in 
circulating PEA levels.[29] Animals with inflammatory pain have greater 
absorption of oral micronized PEA than healthy animals.  PEA plasma levels are 
4.3-fold higher at 15 minutes than healthy animals and overall circulating levels 
are 4.9-fold higher than healthy controls.[59] Spinal cord levels are 26-110-fold 
higher, as measured by [13C]4-micronized PEA.  Inflammation appears to alter 
the spinal cord barrier, allowing greater amounts of PEA to enter the central 
nervous system.[77].  
A 4-arm randomized trial involving Sprague Dawley rats illustrates this point. 
Standardized and micronized radiolabeled PEA was used in healthy animals and 
animals subject to carrageenan paw injections resulting in pain and 
inflammation.[59] The standardized and micronized radiolabeled ([13C]4-
micronized PEA) PEA dose was 30mg/kg in healthy rats and rats subject to 
carrageenan. The inflammatory state significantly increased radiolabeled PEA 
levels relative to healthy controls and oral bioavailability of micronized PEA was 
greater than standardized PEA at the same dose.[59] Significant tissue (paw) 
levels of radiolabeled PEA were seen at 15, 30, and 60 minutes. Tissue levels 
were significantly higher in the carrageenan-treated animals, relative to controls, 
measured at 15, 30, 60 and 360 minutes after PEA administration. Tissue levels 
in those receiving micronized PEA and subject to carrageenan were 6-fold higher 
than healthy controls receiving the same dose. Rats subjected to carrageenan had 
radiolabeled PEA levels in the spinal cord that were 110-fold higher than normal 
controls (11.1 pmol/gm tissue versus 0.10 pmol/gm tissue). Brain levels of 
radiolabeled PEA in rats receiving micronized PEA increased over baseline at 5 
minutes through 60 minutes after administration. Levels though were not higher 
than those seen in healthy controls receiving the same dose of micronized PEA. 
Biopsies of the carrageenan injected paw in animals given oral micronized PEA 
at a dose of 10mg/kg demonstrated reduced mast cell degranulation, reduced 
TNF-alpha levels, IL-6 levels and IL-1 beta levels. Expression of NF-kappa-B 
p65 and cyclooxygenase-2 levels were also reduced compared to controls. These 
histologic findings correlated with reduced edema and hyperalgesia.[59] 
Injections of PEA at a dose of 10mg/kg produces significant levels in the bowel 
and prevents radiation enteritis in mast cell deficient, but not wild type, rats, 
suggesting that significant tissue levels are achieved by systemic administration 
and that paradoxically mast cells are needed to reduce radiation injury. PEA 
benefits in this study appeared to be independent of mast cell modulation.[78]  
Intraperitoneal emulsified micronized PEA at a dose of 10mg/kg in DBA/2 mice 
produces significant brain, blood, heart and retina levels, which persist at 24 and 
48 hours.[79] Brain levels in rodents after oral administration of 30mg/kg 
micronized PEA produces levels, ranging between 21 and 16pmol/gm brain 
tissue, within 15 minutes of administration.[59, 80] Oral administration of 

ACCRU-SC-2102 
 
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radiolabeled micronized PEA at a dose of 100mg/kg produced significant levels 
within the pituitary, hypothalamus and adrenal gland within 20 minutes.[12] 
In summary, though human studies are limited, oral micronized PEA appears to 
be bioavailable and produces measurable plasma levels.  Bioavailability by 
standard in vitro studies is estimated to be 20-30%.  In multiple animal models, 
micronized PEA is rapidly absorbed, and bioavailability is improved by disease 
state. PEA penetrates tissues and produces measurable levels both in the 
peripheral tissues and central nervous system. PEA is catabolized by 2 enzymes 
in tissues (fatty acid amide hydrolase and N-acylethanolamine acid amidase) and 
is not subject to drug-drug interactions. Pharmacokinetics have not been done in 
end-organ failure, but PEA is likely to be safe in hepatic, renal and heart failure 
because of its unique metabolism, absence of active metabolite and its safety. 
1.7.4 
Safety 
PEA has been found to be quite safe by standard in vitro tests, in animal studies 
and clinically.  In vitro, PEA does not induce drug-dependent or a 2-fold increase 
in revertant colonies at 30, 90, 300, and 3000 mcg per plate cultures in the Ames 
test.[14] PEA does not induce biologically significant increases in the percentage 
incidence of micronuclei in binucleated cells at any dose.[14] PEA does not 
cause cytotoxicity as measured by the cytokinesis-block proliferation index.[14] 
PEA does not induce mortality in Sprague Dawley rats at doses as high as 2000 
mg per kg for 15 days.[14] There is no NOEL effect (no observed effect level) at 
doses greater than 1000 mg per kg twice daily.  There was no toxicity noted 
using doses of a 1000 mg per kg for 90 days.[14]  Survival was 100% at 90 days.  
There was no significant loss or gain in weight.  There were no differences in 
blood counts when compared to controls.  There was no biologically significant 
changes in blood chemistries.[14]  There was no gross anatomical or 
histopathological changes noted in treated animals.[14] 
There have been a large number of micronized PEA human trials, largely 
centered on pain.  Daily doses ranged from 300-1200 mg per day.  Thirteen 
studies listed below reported no adverse events, though one study noted an 
adverse event, but was unrelated to PEA.[14] 
Table 1 Clinical Toxicity Noted in PEA Trials 
Study 
Days on Treatment 
Number of Participants 
Toxicity 
Canteri (2010) 
21 
112 
0 
Guida (2010) 
21 
626 
0 
Schifilliti (2014) 
60 
30 
0 
Bacci (2011) 
15 
26 
1 -unrelated to 
PEA 
Pescosolido (2011 
15 
15 
0 
Truini (2011) 
60 
20 
0 
Costaglioda (2014) 
180 
32 
0 
Marini (2012) 
14 
12 
0 

ACCRU-SC-2102 
 
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Barbieri (2010) 
4 
90 
0 
Calabro (2010) 
14 
1 
0 
Conigliaro (2011) 
30 
26 
0 
Affini (2010) 
60 
50 
0 
Desio (2010) 
45 
30 
0 
Three publications are particularly illustrative of the safety and efficacy of PEA 
in treating pain.  A post hoc analysis of a multi-center double-blind, placebo-
controlled, 3-armed trial involved patients with lumbosacral pain; the two 
treatment arms were micronized PEA, 300 and 600mg daily and the third was 
placebo.[81] The duration of treatment was 21 days.  The outcomes were the 
change in the visual analog scale (VAS) (0 no pain 10 severe pain) and the 
Rolan-Morris Disability Questionnaire (RMDQ).  The number needed to treat to 
benefit a single individual (NNT) was calculated using the response criteria of a 
50% improvement in pain relief and a 50% improvement in the RMDQ.  
Attrition due to side effects was determined and the number needed to harm due 
to discontinuation for reasons of adverse effects was the safety outcome.  The 
study registered 626 patients of which 619 were evaluable.  Both treatment arms 
were superior to placebo (P<0.001).  Efficacy was particularly superior in the 
subgroup with neuropathic pain.  For the 300 mg arm, the NNT for pain relief 
was 9 (95% confidence intervals 5-29) and the RMDQ NNT was 6.4 (95% 
confidence interval 4-14) (P<0.02).  For the 600 mg treatment arm the NNT for 
pain relief was 1.7 (95% confidence intervals 1.4 -2) and the RMDQ NNT was 
1.5 (1.4 - 1.7) (P<0.001). The NNH was not different between treatment arms. 
Dropouts were 19 from placebo treatment, 2 from the 300mg treatment arm and 1 
from the 600mg treatment arm.[81] 
There are two meta-analysis published recently.  The first was a meta-analysis of 
pulled raw data available from clinical trials of micronized PEA.[15] The study 
involved trials published between 2010 and 2014.  Patients has had either chronic 
pain or neuropathic pain.  Pain reduction over time was the main outcome.  
Timeframes were divided into baseline (T0), days 7-10 (T1), days 11-14 (T2), 
days 15 through 21 (T3), days 22-45 (T4), and days 46-60 (T5).  Analysis used 
Generalized Linear Mixed Modeling and linear regression.  Cox modeling was 
used to assess the influence of gender, age, pain etiology and study design on 
pain outcomes.  Of 26 clinical trials, 12 met the inclusion criteria.  The number of 
participants were 1484 and doses ranged from 300-1200 mg daily.  Pain 
reduction was seen in both the active and control groups.  The pain reduction was 
superior with PEA and differences were evident at T1 (P<0.05 and) and 
increased over time (P<0.001).  The average reduction in pain using a numerical 
rating scale (0 =no pain 10 = severe pain) was 0.2 points every 2 weeks for 
controls and 1.04 points every 2 weeks for PEA (P<0.001).  Placebo accounted 
for 1% in pain variability over time, whereas PEA accounted for 35% of the 
variability.  Age, gender and pain etiology did not influence responses.  The 
average pain score at 60 days was < 3/10 (0 no pain 10 severe pain) in 81.9% of 
PEA treated individuals, compared to 40.9% for those treated with placebo.[15] 
The second meta-analysis was published in 2017 and involved controlled trials 
using PEA for pain.[33] Randomized trials published up to May 1, 2015 were 
included.  Trials could have either placebo or inactive comparator.  The primary 

ACCRU-SC-2102 
 
12 
 
outcome was the change in the VAS.  Random effects modeling was used for the 
primary outcome and fixed effect modeling was performed for a sensitivity 
analysis.  Publication bias was assessed by funnel plot and Egger’s analysis.  
Trials were grouped by dose, duration of study and trial characteristic.  Meta-
regression was used to assess the effects of dose on outcomes.  Of 25 references, 
10 randomized trials were included in the meta-analysis.  Daily doses ranged 
from 300-800 mg with the majority receiving 600 mg daily.  Of the 1298 patients 
in the meta-analysis, 786 received micronized PEA; 46% of studies had an 
inactive control. PEA was superior to the inactive comparator (WMD = 2.03, 
95% CI: 1.19 – 2.87, z = 4.75, P < 0.001).  By a fixed effect modeling the WMD 
= 2.20, 95% CI: 2.00 – 2.41, z =21.4, P < 0.001).  There was no publication bias.  
Stratified subgroup analysis did not show differences based on trial design.  
There was no response differences between doses.  There was no association of 
efficacy with duration of treatment.  In regard to tolerability, all-cause dropouts 
were reduced in the PEA treated groups, but this was not statistically significant, 
relative to placebo or the inactive comparator (P =0.11).  All-cause dropouts were 
1.1% of patients on PEA and 4.3% in the inactive controls/ placebo treated 
patients.  Adverse effects reported with PEA were gastrointestinal upset in 2 
patients, drowsiness in 1 and heart palpitations in 1 individual. 
In summary, based on two meta-analysis and a large clinical trial, micronized 
PEA is safe, tolerable and efficacious. There are discrepancies in the two meta-
analysis centered dose-response and efficacy over time which will need 
clarification in future studies. 
 
With regards to the effect of PEA on blood tests, the following information is 
available.  Hematology, blood chemistry, and urine analyses have been carried 
out at baseline and at treatment end in 427 patients receiving PEA and showed no 
clinical and statistical differences. (101, 102) In a randomized trial of PEA in 
osteoarthritis versus placebo, (N = 188), the hematological and biochemical 
parameters were in the healthy reference range for all groups at baseline and 
remained stable over the 8 weeks. (103)  Extensive testing has also been done in 
vitro and in animals, demonstrating no toxicity despite very high doses. (104)   
1.8 
CIPN endpoint measurement tools 
Given that this is a pilot trial, we will evaluate neuropathy with a variety of patient-
reported outcome (PRO) tools.  (See Section 11.1)  
1.9 
Toxicity and QOL Endpoint Measurement Tools 
We will utilize the symptom experience diary (Appendix V) and CTCAE version 5.0 
criteria to look for any evidence of toxicity from PEA, understanding that substantial past 
work has suggested that this product does not cause any significant toxicity.  This 
questionnaire will also evaluate QOL changes. (See Sections 11.2 and 11.3 for a detailed 
description of the measurement tools)  
2.0 
Goals 
2.1 
Primary  
The primary objective is to look for evidence of the efficacy of PEA at two different 
doses relative to placebo responses, as a treatment for CIPN.  This is being done to 

ACCRU-SC-2102 
 
13 
 
inform the design of a subsequent phase III trial of PEA for treating bothersome 
established CIPN. 
2.2 
Secondary 
2.2.1 
To assess the safety of PEA at the two study doses. 
2.2.2 
To evaluate changes in patient-reported quality of life from baseline to the end 
of 8 weeks. 
2.3 
Exploratory  
2.3.1 
To explore whether PEA appears to affect cognition in the study patients. 
2.3.2 
To explore the weekly trajectory of CIPN from baseline to 8 weeks. 
2.3.3 
To explore the weekly trajectory of pain using the single-item numerical rating 
scale from baseline to 8 weeks. 
2.3.4 
To explore the weekly patient global impression of change in each treatment 
arm from baseline to 8 weeks.  
2.3.5 
To explore the weekly chemotherapy induced peripheral neuropathy in each 
treatment arm from baseline to 8 weeks. 
2.3.6 
To explore the PEA effects on CIPN20 between two PEA dosage arms. 
2.3.7  To explore the number of recurrent cancer events by study arm 
2.3.8  To explore the overall survival by study arm 
3.0 
Patient Eligibility 
NOTE: Waivers to eligibility criteria are not allowed per ACCRU policy 
3.1 
Registration -- Inclusion Criteria  
3.1.1 
Age ≥ 18 years. 
3.1.2 
ECOG Performance Status 0, 1, 2 (Form available on ACCRU website). 
 
NOTE: Patients with a history of metastatic cancer or an ECOG 
Performance Status of 2 must have lab work (see Section 3.1.9) completed ≤ 
28 days prior to registration. 
3.1.3 
Pain, numbness, tingling or other symptoms of CIPN of ≥ 3 months (90 days) 
duration for which the patient is seeking an intervention.  
3.1.4 
Neurotoxic chemotherapy must have been completed ≥ 3 months (90 days) prior 
to registration and there must be no further planned neurotoxic chemotherapy for 
> 2 months after registration.  
 
Note: The study is limited to those with taxane- and/or platinum-based 
neuropathy.  
3.1.5 
Patient must note tingling, numbness or pain symptoms of at least a four out of 
ten ≤ 7 days prior to registration. 
 
Note: On a 0-10 scale where zero was ‘no problem’ and ten being ‘as bad a 
problem that could be imagined’: how much of a problem has numbness, tingling, 

ACCRU-SC-2102 
 
14 
 
and/or pain in your fingers and/or toes been in the past week? (patient verbal 
report utilizing question 1 in Appendix VI “Peripheral Neuropathy Questions”). 
3.1.6 
Patient must be able to speak, read and comprehend English. 
3.1.7 
For women of childbearing potential only, a negative urine or serum pregnancy 
test done ≤ 14 days prior to registration is required. 
 
A female of childbearing potential is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 12 consecutive months (i.e., has had menses at any 
time in the preceding 12 consecutive months). 
 
NOTE: If the urine test cannot be confirmed as negative, a serum pregnancy test 
will be required. 
3.1.8 
Life expectancy ≥ 6 months. 
3.1.9 
Required Initial Laboratory Values:  Following completion of chemotherapy, 
patients must have had a CBC and serum chemistries, including the following: 
 
Platelet count > 100,000/mm3 
 
Absolute neutrophil count (ANC) ≥ 1,000/mm3 
 
Hemoglobin > 11 g/dL 
 
Serum transaminase [ALT or AST] ≤ 1.2 x upper limit of normal (ULN) 
 
Alkaline phosphatase ≤ 1.2 x ULN 
 
Serum creatinine ≤ 1.2 x ULN   
NOTE: Patients with a history of metastatic cancer or an ECOG 
Performance Status of 2 must have these labs completed ≤ 28 days prior to 
registration. 
3.1.10 Able to swallow oral medication. 
3.1.11 Provide written informed consent ≤ 28 days prior to registration. 
 
3.2 
Registration – Exclusion Criteria 
3.2.1 
Currently receiving neurotoxic chemotherapy for a second cancer or recurrence 
of the primary cancer.  
 
3.2.2 
Impaired decision-making capacity (such as with a diagnosis of dementia or 
 
memory loss). 
 
3.2.3 
Evidence of residual cancer, per routine clinical practice-based parameters. 
 
3.2.4 
Comorbid conditions:  
a) Previous diagnosis of diabetic or another non chemotherapy induced 
peripheral neuropathy. 
b) Previous history of peripheral neuropathy prior to receiving neurotoxic 
chemotherapy.  
c) Neuropathy from HIV infection. Note: Patients with HIV infections are 
eligible as long as they do not have a neuropathy from their viral illness. 

ACCRU-SC-2102 
 
15 
 
 
3.2.5 
Concurrent use of a cannabis product (THC and/or CBD). Patients should have 
 
discontinued these products ≥ 4 weeks prior to registration.   
 
3.2.6 
Current or previous use of PEA.  
 
3.2.7 
Currently receiving or planning to start any of the following agents: opioids, 
 
duloxetine, gabapentin  or pregabalin. Patients are eligible if they discontinue 
 
these medications ≥ 1 week prior to registration. 
 
3.2.8 
Any of the following because the study involves an investigational agent whose 
 
genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn 
 
are unknown: 
 
Pregnant persons 
 
Nursing persons 
 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
 
 
 
 
 
 

 
16 
 
4.0 
Test Schedule 
 
 
Screening 
Active Monitoring Phase 
 
Prior to Registration 
Prior to 
Start of  
Treatment 
(baseline) 
End of each weekly cycle 
(for 8 weeks) 
 
≤ 28 Days 
≤ 14 Days 
≤ 7 Days 
 
 
Tests & Observations
 
 
 
 
 
History
X
CBC and serum 
chemistries, 
including serum 
transaminase [ALT 
or AST], alkaline 
phosphatase and Cr1 
X1 
 
 
 
 
ECOG PS
X
Laboratory Studies 
Serum or Urine HCG2
X2
Patient reported 
measures** 
 
 
 
 
 
EORTC QLQ-CIPN 
20 (Appendix II)
 
 
 
X 
X 
Patient Global 
Impression of 
Change (Appendix 
III)
 
 
 
 
X 
Chemotherapy-
Induced Peripheral 
Neuropathy 
Assessment Tool 
(Appendix IV) 
 
 
 
X 
X 

 
17 
 
Symptom experience 
diary (Appendix V) 
 
 
 
X 
X 
Peripheral Neuropathy 
Question (Appendix 
VI) 
 
 
X4 
X 
X 
Cognitive Functioning 
Assessment 
(Appendix VII) 
 
 
 
X 
X 
Adverse Event 
Assessment3 
 
 
 
 
X3 
Nurse telephone 
contact3 (Appendix 
VIII) 
 
 
 
 
X3 
** 
To be completed using paper booklets. Patient questionnaire booklets are to be available prior to the registration of any patients.  
 
 
The booklet order form is located on the ACCRU website under ‘Manuals and Forms’. Patients are to complete these booklets  
 
 
prior to the end of each week of treatment (See Section 7.2). See appropriate Appendices for samples of the booklets.  
1 
This blood testing is required within the 28 days prior to registration if the patient has a history of metastatic cancer or currently has an 
ECOG Performance Score of 2 (See eligibility criteria 3.1.9). For patients who do not have a history of metastatic cancer or a current 
ECOG Performance Score of 2, this blood testing is to have been completed after the patient finished their chemotherapy per eligibility 
criteria 3.1.4. 
2 
For women of childbearing potential. Must be done ≤ 14 days prior to registration. 
 
3 
Nurse/Research Coordinator will contact the patient at the end of each weekly cycle (+ 2 days) to remind the patient to complete 
questionnaires, answer questions, and to query adverse events. 
4 
To be collected orally (per eligibility criteria 3.1.5) and the response will be documented on the eligibility checklist and in the clinic note 
(per section 18.5).  
 
4.1 
Survival Follow-up  
 
 
 
After completing 8 weeks of treatment, patients will proceed to survival follow-up. A Nurse/Research Coordinator will contact the 
patient to inquire about neuropathy status, disease status, and survival at both 6 months (± 30 days) and 12 months (± 30 days) after 
registration. There will be no additional follow-up after these two timepoints. (Appendix IX) 

 
18 
 
5.0 
Stratification Factors: 
 
Gender: Male vs Female 
 
Prior Chemotherapy Received:  Any Taxane ± carboplatin ± other agents versus 
Oxaliplatin based versus other (never received a taxane nor oxaliplatin) 
6.0 
Registration/Randomization Procedures 
 
6.1 
Site Procedures 
 
6.1.1 
Study staff will need to complete the required training prior to gaining access to 
the registration application. This is located on the ACCRU web page at 
Refer to Study Resources  Applications. Near the bottom of 
the page there will be a link to the “Research Registration Application Training.” 
After training is complete, study staff must complete the “Attestation of 
Training” and send to the ACCRU Registration Office at 
 
 
6.1.2 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. Approvals should be uploaded using 
Florence online.  
 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals 
should be uploaded using the Florence online. If the necessary documentation is 
not submitted in advance of attempting patient registration, the randomization 
will not be accepted and the patient may not be enrolled in the protocol until the 
situation is resolved.  
 
 
Submission of annual IRB approvals is required until the study has been closed 
through your IRB.  
6.2 
Registration Procedures 
 
6.2.1 
To register a patient, access the ACCRU web page at 
 go to the 
Study Resources  Application section and click on “Registration” and enter the 
registration application.   The registration application is available 24 hours a day, 
7 days a week.  Back up and/or system support contact information is available 
on the Web site.  If unable to access the Web site, email the Academic and 
Community Cancer Research United (ACCRU) Registration Office at  
 between the hours of 8 a.m. and 4:30 p.m. Central Time 
(Monday through Friday). 
 
Instructions for the registration application are available on the above web page 
under the Study Resources  Application section. Please refer to the “Research 
Registration Application Training” or Quick Reference Guide for instructions.  
Prior to initiation of protocol treatment, this process must be completed in its entirety 
and an ACCRU subject ID number must be available as noted in the instructions.  It 
is the responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent.  

 
19 
 
Patient registration via the registration application can be confirmed in any of the 
following ways: 
 
Contact the ACCRU Registration Officer
If the patient 
was fully registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
 
Refer to the Research Registration Application training on the ACCRU 
website under Study Resources  Applications. 
 
6.2.2 Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
6.2.3 
Treatment cannot begin prior to registration and must begin  14 days after 
registration. 
 
6.2.4 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.2.5 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of an oncologist.  
 
6.2.6 
Study drug is available on site.  
 
6.2.7 
Patient questionnaire booklet is available on site. 
 
6.3 
Randomization Procedures  
 
6.3.1 
The factors defined in Section 5.0 will be used as stratification factors. 
 
6.3.2  After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups [105]. 
 
 
Palmitoylethanolamide: 400 mg (1 capsule daily) PO for 8 weeks 
 
Palmitoylethanolamide: 800 mg (1 400mg capsule twice daily) PO for 8 
weeks 

 
20 
 
 
Placebo: 1 capsule PO daily for 8 weeks 
 
Placebo: 1 capsule PO twice daily for 8 weeks 
 
6.4 
Procedures for Double-Blinding the Treatment Assignment  
 
6.4.1 
After the treatment assignment has been ascertained by the 
registration/randomization application, the registration specialist will notify the 
designated unblinded data manager/nurse/pharmacist at the patient’s institution. 
The name of this contact person is to be entered in the designated space on the 
eligibility checklist, so the Registration Office personnel have it for each patient 
at the time of randomization. Make sure this contact person will be available at 
the time of randomization so he or she can take a call from the registration 
specialist if necessary. This contact person may not be involved in assessing 
adverse events or any other outcome measure and should not be the same person 
listed on page one of the Eligibility Checklist Form as the person completing the 
form. The last page of the Eligibility Checklist Form should provide the e-mail 
address and the appropriate contact information (including phone number). The 
registration specialist will then communicate the treatment assignment to the 
designated contact at the patient’s institution. 
 
6.4.2 
The treatment assignment will be to palmitoylethanolamide 400 mg once daily, 
palmitoylethanolamide 400 mg twice daily, placebo once daily, or placebo twice 
daily. Innexus Nutraceuticals will provide supplies labeled for investigational use 
to McKesson Specialty Pharmacy’s Clinical Research Services. Each 
participating institution will order the drug from McKesson using the protocol-
specific Drug Order Request Form. Each participating institution will be 
responsible for monitoring drug supplies and will use the Drug Order Request 
Form to order additional supplies as needed. Upon receipt of orders, McKesson 
Specialty Pharmacy’s Clinical Research Services will send bulk supply to 
participating institutions. The palmitoylethanolamide/placebo drug supplies will 
be prepared and labeled by the unblinded pharmacist per Section 7.1 so that the 
contents are not discernible to the person administering the treatment. 
 
6.4.3 
The unblinded pharmacist will maintain records that indicate the identity of the 
patient and their corresponding treatment assignment. 
 
7.0 
Treatment Plan/Intervention 
Protocol treatment is to begin ≤ 14 days of registration.  
This is a randomized double-blind trial. See Section 15.1 for drug procurement instructions.  
Patients with peripheral neuropathy either from a platinum or taxane based chemotherapy will be 
randomized if eligible to one of four treatment arms: 
 
 

 
21 
 
Agent 
Dose 
Route  
Day  
Palmitoylethanolamide 
(PEA) 
400 mg (1 capsule 
daily) 
PO 
Daily for 8 
weeks 
Palmitoylethanolamide 
(PEA) 
800 mg (1 400 mg 
capsule twice 
daily) 
PO 
Daily for 8 
weeks 
Placebo 
1 capsule daily 
PO 
Daily for 8 
weeks 
Placebo 
1 capsule twice 
daily 
PO 
Daily for 8 
weeks 
 
Medications will be taken once or twice daily depending on randomization.  Assessment of 
neuropathy, side effects and cognitive function will occur weekly. 
 
7.1 
Palmitoylethanolamide (PEA)/Placebo  
Beginning on Day 1 of the study, and for eight weeks, patients will be instructed to take 
one of the following: 
 
Palmitoylethanolamide (400 mg) or placebo: 1 capsule by mouth once in the 
morning daily for 8 weeks  
OR 
 
Palmitoylethanolamide (400 mg) or placebo: 1 capsule by mouth once in the 
morning and once in the evening daily for 8 weeks 
  
7.2 
Submission of Patient Completed Measures (Booklets) 
Patient-completed questionnaire booklets for this study are to be ordered prior to the 
registration of any patients. The booklet order form is located on the ACCRU website 
under ‘Manuals and Forms. Samples of questionnaire booklets are available in 
Appendices II-VII for reference and IRB submission only. Booklets must be given to 
patients to complete and patients should be instructed to return the booklets to site staff 
either in person or by mail and site staff will enter patient responses into Medidata Rave. 
At visits in which booklets are to be completed, the booklet should be given to and 
completed by the patient before any discussion of the patient’s health status or test 
results. The PRO submission schedule is provided in the Study Calendar.  
Baseline Booklet: The baseline questionnaire booklet should be completed in clinic on 
the same day as registration and returned to study staff. In the event the patient is unable 
to complete while in the clinic, the patient may complete at home and return by mail prior 
to starting the study medication. 
Weekly Booklets: Questionnaire booklet(s) will be provided to patients to complete at 
home on a weekly basis for a total of eight weeks. Before the booklets are given to the 
patients, the nurse/study assistant will label each booklet with the week number and the 
anticipated 7-day weekly cycle start dates, in chronological order. Patients should be 
instructed to return the booklets by mail weekly. If, by chance, the patient has a regularly 
scheduled clinic visit at any time during the study period, the patient could return that 

 
22 
 
week’s questionnaire during the clinic visit. Institutions must provide patients with 
sufficient self-addressed stamped envelopes for this purpose. Site staff will enter patient 
responses into Rave upon receipt of the completed booklets. 
 
Verbal administration of the measures for visually impaired patients is permitted if the 
 
measure and verbal administration of the measure is conducted in a language 
 
understandable to the patients.  
7.3 
Unblinding Procedures 
 
Unblinding during active study treatment can be done only in cases of an emergency. 
 
Follow the directions below to unblind patient treatment. Please note that if a treatment 
 
assignment is unblinded, the patient must discontinue protocol therapy. 
 
7.3.1 
Emergency Unblinding Procedures 
Examples of emergencies include 1) a life-threatening unexpected adverse event 
that is at least possibly related to the investigational agent and for which 
unblinding would influence treatment decisions; or 2) medication error, such as 
accidental overdose.  
In the event of an emergency, email the ACCRU Registration Office at 
 to break the code on Monday through Friday, 8:00 a.m. to 
4:30 p.m. Central Time. If the code must be broken after hours, assume the 
patient was assigned to active treatment and treat accordingly. Send an email to 
the ACCRU Registration Office informing them of the need to un-blind a patient. 
Provide your contact information so that ACCRU Registration Office personnel 
can respond to the email the next business day. 
 
7.3.2 
Study Completion Unblinding 
 
On a case by case basis, if in the judgement of the treating physician, it would be 
helpful for the future clinical care of the individual patient, the code may be 
broken after the patient has completed the study. That is, after the patient has 
completed study treatment and mailed in all of the required study questionnaires. 
The ACCRU Registration Office may be contacted to find out which study 
therapy the patient was receiving. This would allow for the individual patients to 
choose whether to continue taking active PEA or to start it. This treatment would 
be considered off study and patients should discuss with their primary cancer 
physician. Patients would need to purchase palmitoylethanolamide on their own 
terms.  
8.0 
Dose and Treatment Modifications  
8.1 
Dose Modifications 
There are no known toxicities related to the study medication. However, patients who 
have an unacceptable toxicity which they attribute to the study medication, should 
discontinue study treatment. Clinical investigators may use clinical judgment to stop 
treatment for suspected adverse events. This should be decided and done prior to 
breaking the study code for an individual patient.  

 
23 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Prohibited Concomitant Medications/Therapy 
 
 
 
Patients should not receive any other treatment which would be considered treatment for 
peripheral neuropathy or impact the primary endpoint. This includes opioids, duloxetine, 
gabapentin, pregabalin, or PEA obtained outside of this study. 
 
 
Patients should not receive other cannabinoids (CBD or THC) by any route for 4 weeks 
prior to registration or during the eight-week study period.  If it’s discovered a patient is 
receiving a cannabinoid while on active study treatment, this will need to be reported in 
the case report forms. Patients will be asked to discontinue the cannabinoid, if patient 
declines, they will be removed from study and proceed to Survival Follow-up (Section 
13.0). 
 
 
Patients should not receive other PPAR- α agonists used to treat high triglycerides 
including clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate as these may 
interact with the investigational agent, PEA. 
 
 
Patients should not receive any neurotoxic chemotherapy ≥ 3 months (90 days) prior to 
registration or for > 2 months after registration. If the patient develops disease recurrence 
whereby such treatment is indicated, the patient will be taken off active study treatment 
and proceed to Survival Follow-up (see Section 13.0).  
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all adverse events to the sponsor as 
described within the protocol. Refer to the adverse event and serious adverse event sections of the 
protocol for detailed information. 
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
 
Any suspected adverse reaction that is both serious and unexpected.  
 
Any findings from laboratory animal or in vitro testing that suggest a significant risk 
for human subjects, including reports of mutagenicity, teratogenicity, or 
carcinogenicity.  
 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted 
by the sponsor, that suggest a significant risk in humans exposed to the drug.  
 
Any clinically important increase in the rate of a serious suspected adverse reaction 
over the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  
 

 
24 
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means in 
order to facilitate the review of safety data (may be requested by the FDA or the 
sponsor).  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
 
b. Identify the grade and severity of the event using the CTCAE version 5.0.   
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, treatment 
or procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.5 and 
18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT). 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 
 

 
25 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, 
(if an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 15.0 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal 
relationship between the drug/device and the adverse event.  
 
10.3.1 
Death 
 
 Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
 Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
 
 Reportable categories of Death  
 
 
 
Death attributable to a CTCAE term. 
 
 
Death Neonatal:  A disorder characterized by cessation of 

 
26 
 
life during the first 28 days of life. 
 
 
 
Death NOS:  A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
 
 
Sudden death NOS:  A sudden (defined as instant or within 
one hour of the onset of symptoms) or an unobserved 
cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
 
 
 
Death due to progressive disease that cannot be attributed to 
a CTCAE term associated with Grade 5 should be reported 
as Grade 5 “Disease progression” under the system organ 
class (SOC) of General Disorders and Administration Site 
Conditions.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
 
10.3.2 
Secondary Malignancy 
 
 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE to be reported. Three options are available to describe the 
event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting mechanisms 
outlined in each protocol. 
 
10.3.3 
Second Malignancy 
 
 
A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting. 

 
27 
 
 
10.3.4 New Malignancies 
 
 
All new malignancies must be reported whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should 
be reported, i.e. solid tumors (including non-melanoma skin malignancies), 
hematologic malignancies, myelodysplastic syndrome/acute myelogenous 
leukemia, and in situ tumors. 
 
 Whenever possible, the expedited report for new malignancies should 
include tumor pathology, history or prior tumors, prior 
treatment/current treatment including duration, any associated risk 
factors or evidence regarding how long the new malignancy may 
have been present, when and how the new malignancy was detected, 
molecular characterization or cytogenetics of the original tumor (if 
available) and of any new tumor, and new malignancy treatment and 
outcome, if available.  
 
10.3.5 Pregnancy  
 
Prior to obtaining private information about a pregnant woman and her infant, 
the investigator must obtain consent from the pregnant woman and the 
newborn infant’s parent or legal guardian before any data collection can occur.  
A consent form will need to be submitted to the IRB for these subjects if a 
pregnancy occurs. If informed consent is not obtained, no information may be 
collected. 
 
In cases of fetal death, miscarriage or abortion the mother is the patient. In 
cases where the child/fetus experiences a serious adverse event other than fetal 
death, the child/fetus is the patient. 
 
NOTE: When submitting 
 
 the potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section. Include any 
available medical documentation.  
 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
 
 
10.4.1 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for  
 
 
 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the  
 
 
 
Last Administration of the Investigational Agent/Intervention1, 2 

 
28 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes
Grade 2 
Timeframes
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Special Instructions:  
 
Follow site-specific reporting guidelines. 
 
Submit the ACCRU Adverse Event Expedited Report Form to the ACCRU SAE Coordinator via 
email 
. The ACCRU SAE Coordinator will forward to 
 
 via email: 
 
 
The ACCRU IND Coordinator will assist the sponsor-investigator in notifying the FDA if 
required. 

 
29 
 
10.5 
Other Required Reporting 
 
10.5.1 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. 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 subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, 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 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events.  In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies.   
 
 
10.5.2 Baseline and Adverse Events Evaluations 
 
 
Not applicable.  
 
10.5.3   Submit via appropriate Academic and Community Cancer Research United 
(ACCRU) Case Report Forms (i.e., paper or electronic, as applicable) the 
following AEs experienced by a patient and not specified in Section 10.5: 
 
10.5.3.1 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
10.5.3.2 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure 
 
10.5.3.3 Grade 5 AEs (Deaths) 

 
30 
 
 
10.5.3.3.1 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.5.3.3.2 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
11.0 
Treatment Evaluation/Measures 
A description of the patient reported measures is included below. It will take patients 
approximately ten to fifteen minutes to complete the questionnaires.  
11.1 
CIPN endpoint measurement tools 
We will evaluate neuropathy with a variety of patient-reported outcome (PRO) tools.  
These include the following three assessment items.  
11.1.1 EORTC QLQ-CIPN20 (Appendix II) 
The EORTC QLQ-CIPN20 [82-85] (CIPN20) is a 20-item PRO questionnaire 
originally designed to supplement the EORTC Quality of Life Questionnaire. 
Based on the initially hypothesized factor structure, it contains 9 items assessing 
sensory neuropathy items, 8 assessing motor function, and 3 assessing autonomic 
neuropathy. Items are scored from 1-4 with 1 representing “not at all” and 4 
“very much.” Item scores are summed to obtain subscale scores. However, given 
conflicting evidence regarding the validity of this three-factor structure, recent 
evidence suggests that all items can be summed to obtain a total CIPN score. 
Scores can be linearly converted to a 0-100 scale with higher scores reflecting 
less CIPN. The published literature provide evidence of its internal consistency 
and stability reliability, sensitivity, convergent and contrasting group validity, 
and responsiveness; nine studies conducted across multiple countries support its 
strong psychometric properties [86, 87]. This is completed prior to treatment and 
at the end of every week of treatment for eight weeks.  
11.1.2 Patient Global Impression of Change (Appendix III)   
The Patient Global Impression of Change (PGIC) is a tool that came out of the 
Clinical Global Impressions scale (CGI).  The CGI was initially published in 
1976 by the National Institute of Mental Health (US). The PGIC tool was taken 
from the CGI and adapted to be completed by patients, therefore becoming a 
PRO measurement tool [88]. This is completed at the end of every week of 
treatment for eight weeks 
11.1.3 Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (Appendix IV) 
The Chemotherapy-Induced Peripheral Neuropathy Assessment Tool consists of 
14 items that might be affected by peripheral neuropathy.  Patients are asked to 
complete a numerical rating score from 0-10 related to symptoms “not at all 
interfering” to “completely interfering” based on the patient’s neuropathy 
symptoms.  This tool has been validated [89, 90]. This is completed prior to 
treatment and at the end of every week of treatment for eight weeks. 

 
31 
 
11.2 
Toxicity and QOL Endpoint Measurement Tools 
We will utilize the symptom experience diary (Appendix V) and CTCAE version 5.0 
criteria to look for any evidence of toxicity from PEA, understanding that substantial past 
work has suggested that this product does not cause any significant toxicity.  This 
questionnaire will also evaluate QOL changes. 
11.2.1 Peripheral Neuropathy Questions (Appendix VI) 
This appendix provides the question that is to be verbally asked, to prospective 
protocol candidates, to judge whether or not they have enough neuropathy to 
participate in this clinical trial. This question will be asked prior to enrollment, 
and this question and the specific question with regard to pain in fingers/hand and 
toes/feet will be asked at the end of every week.  
11.2.2 Cognitive Function 
PEA (N-Palmitoylethanolamide) may have an influence on cognitive function by 
indirect evidence. There are multiple scales that have been used to assess 
cognitive function [91-97]. We have decided to have patients complete two 
questions to assess this (Appendix VII). This assessment will be completed prior 
to treatment and at the end of every week of treatment for eight weeks.  
11.3 
Nurse, clinician, or study assistant Telephone Contact (Appendix VIII)  
All patients will receive weekly phone calls from study staff, to document compliance 
with study drug, encourage completion of requisite study questionnaires, and address any 
patient concerns or problems and assess adverse events. 
12.0 
Descriptive Factors 
 
None 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
13.1 
Treatment Duration/Off protocol treatment 
Protocol treatment is to continue for eight weeks. If patient discontinues treatment for any 
reason prior to the end of the eight weeks, they will proceed to Survival Follow-up per 
Section 4.1 until 1 year post-registration. All attempts should be made to collect patient 
questionnaires until the last date the patient received any protocol treatment.  
 
13.2 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or 
the patient no longer wishes to continue protocol therapy, protocol therapy shall be 
discontinued. In this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
 
13.3 
Ineligible  
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
 
 
If the patient received treatment, the patient may continue treatment at the discretion 

 
32 
 
of the physician as long as there are no safety concerns. The patient will continue in 
the Active Monitoring/Treatment phase of the study, as per section 4.0 of the 
protocol.   
 
 
If the patient never received treatment, on-study material and the Off Treatment form 
must be submitted. No further data submission is necessary. 
 
13.4 
Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. The patient may continue treatment at the discretion of the physician as 
long as there are no safety concerns. The patient will continue in the Active 
Monitoring/Treatment phase of the study, as per section 4.0 of the protocol, and all data 
submission should continue per protocol. If the patient does not continue with treatment, 
the patient will go off treatment and be followed in Survival Follow-up. 
13.5 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the Off Treatment form must be 
submitted. No further data submission is necessary. 
14.0  
Body Fluid Biospecimens 
 
None. 
15.0 
Drug Information 
 
 15.1 
Palmitoylethanolamide (OptiPEA®) 
 
 
 
IND number 155458 
 
Investigator brochure available on ACCRU website 
 
15.1.1 Background:  
Palmitoylethanolamide, or PEA, is a naturally occurring fatty acid amide and 
belongs to the class of organic compounds known as carboximidic acids. It is an 
Autacoid Local Injury Antagonist amide (ALIAmide) which are endogenous 
bioactive ethanolamides with anti-inflammatory properties. These compounds are 
produced as a reaction to injury and are generated and metabolized in the same 
cells and tissue. 
 
15.1.2 Formulation:  
 
Palmitoylethanolamide (OptiPEA®) is supplied as capsules containing 400 mg of 
 
non-micronized PEA. There are no excipients in the PEA capsules. 
 
15.1.3 Preparation and storage: 
 
  
Store at room temperature. Keep container tightly closed. Store in accordance 
with information listed on the product insert. 
 
15.1.4 Administration:  

 
33 
 
Palmitoylethanolamide (OptiPEA®) will be provided as 400 mg capsules 
supplied in bottles containing 30 capsules. It can be administered either once or 
twice daily as directed by the protocol, with food to maximize absorption. 
Capsules should be swallowed whole and not crushed or opened. 
 
15.1.5 Pharmacokinetic information: 
a) Absorption – Human intestinal Caco-2 cell lines are widely used in vitro to 
estimate drug bioavailability. For micronized PEA, initial absorption starts at 30 
minutes and maximum absorption peaks at 3 hours. Bioavailability is 
approximately 20-30%. This study uses non-micronized PEA. Most clinical 
studies have used some form of micronized (e.g., co- or ultra-micronized) PEA. 
However, there are no head-to-head clinical comparisons of non-micronized vs. 
micronized formulations of PEA, and so evidence for superiority of one 
formulation over the other remains lacking according to the latest reviews. 
Unmicronized, micronized, and ultra-micronized PEA formulations have all 
shown to be absorbed following oral administration but there is little data 
available concerning the actual absorption phase or whether the rate of 
absorption can be improved. There is no information in the literature about the 
bioavailability of PEA or, arguably more importantly, how bioavailability varies 
between individuals. 
b) Distribution – PEA is likely to show considerable plasma protein binding. It 
does penetrate peripheral tissue and the central nervous system 
c) Metabolism – Tissue enzymatic degradation from PEA  palmitic acid  
incorporation into phospholipids. The extent to which orally or topically 
administered PEA is hydrolyzed to palmitic acid prior to its excretion from the 
body, is unclarified.  
d) Excretion – Unknown.    
 
15.1.6 Potential Drug Interactions: Based on its mechanism, PEA may be considered  
 
 
likely to interact with other PPAR- α agonists use to treat high triglycerides  
 
 
including clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate.  
 
 
However, no data on interactions with PEA are available and none have been  
 
 
reported.  
 
15.1.7 Known potential toxicities: PEA is generally considered safe, and without  
 
 
adverse drug reactions. Infrequent reports of gastrointestinal upset, drowsiness,  
 
 
and heart palpitations were noted in studies with PEA. Individual cases of urinary 
 
 
tract infection, paralytic ileus, cholecystolithiasis, fungal infection, and erysipelas 
 
 
(bacterial skin infection) causing hospitalization have also been reported.  
 
15.1.8 Drug procurement: Innexus Nutraceuticals will supply palmitoylethanolamide  
 
 
(PEA) free of charge to study participants. This agent will be supplied to   
 
 
McKesson Specialty Pharmacy’s Clinical Research Services. Each participating  
 
 
ACCRU treating location will order the drug from McKesson Specialty   
 
 
Pharmacy’s Clinical Research Services. Submit the Drug Order Request Form  
 
 
(found on the ACCRU website) :  
 
 
 
 
 
 
 
 
 

 
34 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of palmitoylethanolamide (PEA) and will use the Drug Order Request 
Form to order additional supplies as needed. 
 
 
Outdated or remaining drug is to be destroyed on-site as per institutional   
 
 
procedures. 
15.1.9 Each participating institution may ship Study Product/Placebo directly to their 
patients. If the site’s standard operating procedures allow. All local site procedures 
should be followed, and accurate accountability logs should be maintained. 
 
 
NOTE: All sites are responsible for shipping material and shipping cost. 
 
15.2.0. Nursing guidelines: 
 15.2.0.1.1PEA may interact with other similar drugs (such as gemfibrozil, 
fenofibrate, and clofibrate). Assess patients’ concomitant medications 
and any over the counter supplements. 
 
15.2.0.2Overall PEA has been well-tolerated with no major side effects, instruct 
 
patient to report any side effect to the study team immediately.  
15.2 
Placebo 
15.2.1 Formulation: Matched placebo capsules are provided in identical PEA-Placebo 
labeled bottles for dispensing. Each placebo capsule contains 400mg dextrose in 
a size 0 transparent Hydroxypropyl methylcellulose (HPMC) capsule.  
 
15.2.2 Storage: Products are to be stored in the original container below 25°C.   
 
 
Containers should be stored tightly closed. 
 
16.0 
Statistical Considerations 
16.1 
Statistical Design 
This trial is designed as a randomized placebo-controlled pilot trial with the primary 
objective of estimating the efficacy of two dose levels of PEA to inform the design of a 
future phase III trial for treatment of chemotherapy-induced peripheral neuropathy 
(CIPN). Patients will be randomized 2:2:1:1 to receive either 400 mg of PEA (one 400 
mg capsule), 800 mg PEA (two 400 mg capsules), 1 placebo capsule, or 2 placebo 
capsules, respectively. The two placebo arms are included in this study to ensure that 
there is a matched number of capsules for each of the PEA arms; however, all placebo 
patients will be analyzed as one group (a combined placebo arm).  The efficacy of the 
two dose levels of PEA will be estimated as the difference between each dose level of 
PEA compared to the combined placebo arm. 
16.2 
Sample size, Accrual time and Study Duration 
16.2.1 Sample size 
As this is a pilot trial to estimate the efficacy of PEA, the sample size is based on 
feasibility considerations and estimation precision. We plan to accrue a total of 
88 patients (consisting of 78 evaluable patients + 10% dropout due to 
cancellation or ineligibility). Based on our previous trial experience [98], by 
assuming the standard deviation of the 0-100 scale transformed CIPN20 change 
score is 15 in each treatment arm. With this assumption, 26 patients per PEA arm 
and 26 total patients for the combined placebo arm (pooling all patients receiving 

 
35 
 
placebo together for statistical analysis) allows estimation of the difference 
between two arms, of the CIPN20 score change from baseline to 8 weeks, with a 
95% two-sided confidence interval width of 16.8 points.  
16.2.2 Accrual time and study duration 
We assume that the accrual rate will be about 6 patients per month; if true, the 
anticipated study period for accruing 88 patients will be 15 months. With data 
from the primary endpoint maturing 8 weeks later, the primary analysis can begin 
approximately 17 months after the trial begins; as soon as all patients have 
completed 8 weeks of treatment and submitted QOL booklets or have gone off 
protocol treatment. 
16.3 
Primary Endpoint Analysis Plan 
16.3.1 Primary endpoint analysis  
The primary endpoint is the CIPN20 score (Appendix II).  The CIPN20 
questionnaire will be scored and summarized at each time point for each patient 
(see Section 11.1).  The change from baseline to 8 weeks will then be calculated 
for each patient.  The mean (standard deviation) and median (range) of the 
change will be calculated for each PEA arm and the combined placebo arm.  The 
difference in change scores between each PEA arm and the combined placebo 
will be estimated along with a 95% confidence interval. For the primary analysis, 
the CIPN20 analysis dataset will include all eligible patients who are 
randomized, initiated treatment, and completed the baseline questionnaire. For 
patients who go off protocol treatment before 8 weeks, the score at their final 
observation will be used to calculate the change. For patients who do not have 
any post baseline data, they will be considered to have no change from baseline. 
Sensitivity analysis based on imputation of missing data as described in Section 
16.5 will be performed using similar methods.  
16.3.2 Interim analysis for primary endpoint 
Because this study is a pilot randomized parallel group trial to look for evidence 
of the efficacy of PEA, no interim data analysis is planned.  
16.4 
Secondary/Exploratory Analysis Plans 
The safety analysis dataset is defined as all eligible patients who are randomized and had 
at least one dose of treatment (PEA or placebo). 
The efficacy analysis dataset for the secondary/exploratory analysis will be based on the 
CIPN20 primary endpoint analysis dataset. 
16.4.1 Secondary endpoint analysis  
16.4.1.1Adverse events by patient will be summarized by frequencies and 
severity using CTCAE v5.0. The proportion of patients who experience 
at least one grade 3+ adverse event (regardless of attribution) will be 
reported. The overall adverse event rates for grade 3 or higher adverse 
events will be compared across the three arms (the two PEA arms and 
combined placebo) using a Chi-squared or Fisher’s Exact tests as 
appropriate.   
16.4.1.2The difference in change of QOL (Question 3 Appendix V, PRO-QOL) 
from baseline to 8 weeks will be calculated for each patient. The mean 
and standard deviation of the change will be reported for each PEA arm 

 
36 
 
and the combined placebo arm. Additional analysis using data collected 
from the Symptom Experience Diary may be performed. For patients 
who go off protocol treatment before 8 weeks, the question 3 response at 
their final observation will be used to calculate the change. For patients 
who do not have any post baseline data, they will be considered to have 
no change from baseline.  
16.4.2 Exploratory endpoint analysis 
16.4.2.1 The two cognitive items of the Cognitive Functioning Assessment 
(Appendix VII) will be summarized by mean (SD) and median (range) at 
each time point  for each PEA arm and the combined placebo arm.  The 
mean change from baseline to 8 weeks will be estimated along with the 
95% confidence interval for each PEA arm and the combine placebo 
arm.  
16.4.2.2The weekly CIPN20 scores will be summarized at each time point by 
mean (SD) and median (range) and will be plotted longitudinally for 
each PEA arm and the combine placebo arm.  
16.4.2.3The weekly pain scores (Appendix VI) will be summarized at each time 
point by mean (SD) and median (range) and will be plotted 
longitudinally for each PEA arm and the combined placebo arm.  
16.4.2.4Items of the Global Impression of Change tool (Appendix III) will be 
summarized by frequency (percentage) of each level at each time point 
for each PEA arm and the combine placebo arm.  Bar plots for each PEA 
arm and the combined placebo arm of frequency over time will be 
constructed.  
16.4.2.5The Chemotherapy Induced Peripheral Neuropathy Assessment Tool 
(Appendix IV) will be summarized by mean (SD) and median (range) at 
each time point for each PEA arm and the combine placebo arm.  
16.4.2.6 Using the changes scores constructed for the primary endpoint, the 
difference in CIPN20 change scores between the two PEA dosage arms 
will be estimated along with a 95% confidence interval. 
16.4.2.7Evidence of disease recurrence and the date of recurrence will be asked 
by nurse at the 6 and 12 months’ follow-up (Appendix IX). The number 
of events and percentage will be reported by each PEA arm and 
combined placebo arm. No hypothesis test will be performed between 
arms.  
16.4.2.8Overall survival is defined as the time from registration to death due to 
any cause. For each PEA arm and combined placebo arm, the 
distributions of OS time will be estimated using the Kaplan-Meier 
method. Log-rank test will be used to compare the survival distributions 
between each PEA and the combined placebo arm.  
16.5 
Missing Data 
We will examine the mechanisms of missing data if the proportion of missing 
assessments for the primary endpoint is not small (≥ 10%). Graphical presentation, 
correlation analysis (Kendall's) and logistic regression will be performed to examine 
whether the missing data mechanism depends on the covariates (patient characteristics 

 
37 
 
and other baseline risk factors), observed patient-reported outcome (PRO) scores, and 
missing PRO scores.  
If the missingness is completely at random (MCAR), complete case analysis will be 
conducted.  
If the missingness depends on covariates and observed PRO scores (missing at random, 
MAR) [99] [100], the data will be analyzed using the (generalized) linear mixed models 
with patient as the random effect and treatment along with all factors associated with data 
missingness will be included as predictors in the models. [100]. 
If there are indications that the missingness is not at random (MNAR),, we will explore 
advanced models that consider both longitudinal PRO assessments and missing data 
mechanism, such as pattern mixture model and selection model[100]. 
16.6 
Study Monitoring 
16.6.1 Adverse Event Stopping Rule  
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below.  
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e., an adverse 
event with attribute specified as “possible”, “probable”, or “definite”) that satisfy 
the following:  
 
If 2 or more patients in the first 10 treated patients in any study arm (or 
20% of all patients after 10 are accrued) experience a grade 3 or higher 
adverse event and the event rate is higher in the active treatment arm.  
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event.  
16.7 
Study Reporting  
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN.   
This study will be monitored by the Mayo Data Safety Monitoring Board (DSMB). 
Reports containing efficacy, adverse event, and administrative information will be 
provided to the DSMB every 6 months as per NCI guidelines.  
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrials.gov” web site. The Primary and Secondary 
Endpoints (i.e., “Outcome Measures”) along with other required information for this 
study will be reported on ClinicalTrials.gov.  
 

 
38 
 
16.8 
Inclusion of Women and Minorities 
We expect about 17% of patients will be classified as minorities by race and ethnicity. 
Expected sizes of race by ethnicity subsets for patients randomized to this study are 
shown in the following table. 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
5 
5 
0 
0 
10 
White 
42 
31 
2 
1 
76 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
48 
37 
2 
1 
88 
Ethnic Categories:  
• 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term 
“Spanish origin” can also be used in addition to “Hispanic or Latino.” 
• 
Not Hispanic or Latino 
• 
Racial Categories 
 
• 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
• 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam. (Note: Individuals from the Philippine Islands have been recorded 
as Pacific Islanders in previous data collection strategies.)  
• 
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
• 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
• 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 

 
39 
 
17.0 
Pathology Considerations/Tissue Biospecimens 
 
None. 
 
18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
 
NOTE: If a patient is still alive 1 year after registration, no further follow-up is required. 
 
18.2 
Survival Follow-up 
See Section 4.1  
 
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
 
18.4 
Site responsibilities 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
ACCRU registration number, and ACCRU protocol number. All PHI must be redacted 
from any documentation.  
 
18.5 
Supporting documentation 
Upload a copy of documentation in RAVE on the Supporting Documentation Form. 
 
Baseline: The following documents are required for diagnosis and eligibility verification: 
Clinic note including description of prior chemotherapy and neuropathy status. These 
documents should be submitted within 14 days of registration.  
 
 
 
18.6 
Labeling of materials 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
ACCRU registration number, and ACCRU protocol number. Patient’s name must be 
removed. 
 
18.7 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
ACCRU website. Only site staff rostered with the Rave CRA role will have access to 
these reports. 

 
40 
 
 
All data must be entered by Remote Date Entry (RDE) and completed by qualified and authorized 
personnel. Access the RAVE RDE system through the iMedidata portal at 
All data on the CRF must reflect the corresponding source 
document. Please refer to the ACCRU website for instructions 
  
 
19.0 
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and  
 
 
regional coverage policies, to determine which items are standard of care and which are  
 
 
research at their site. Refer to the payment synopsis for funding provided per accrual for  
 
 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
 
 

 
41 
 
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Appendix I 
Page 1 of 2 
47 
 
Appendix I: ACCRU-SC-2102 PATIENT INFORMATION SHEET 
 
Patient Completed Questionnaire Booklet 
Baseline 
 
You will be given booklets to complete for this study. This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer. Your answers help us to better 
understand how the treatment you are receiving is affecting the way you feel.  
1. You are being asked to complete a questionnaire booklet for this study. This booklet must be 
completed on the day you enroll in the study.  
2. This booklet contains the following questionnaire(s):  
a. EORTC QLQ-CIPN20 Instrument 
b. Chemotherapy Induced Peripheral Neuropathy Assessment Tool 
c. Symptom Experience Diary (Baseline) 
d. Peripheral Neuropathy Question 
e. Cognitive Functioning Assessment 
3. Directions on how to complete each set of questions are written at the top of the page.  
4. You will be given the nurse’s or study coordinator’s name and telephone number. You can 
call any time with any concerns or questions.  
5. Please complete the booklet and return it to your study staff. If returning by mail, please use 
the self-addressed and stamped envelopes provided with the questionnaires. It is very 
important that you return the booklet to us.  
 
Thank you for taking the time to help us. 
 
 

Appendix I 
Page 2 of 2 
48 
 
Appendix I: ACCRU-SC-2102 PATIENT INFORMATION SHEET 
 
Patient Completed Questionnaire Booklet 
During Treatment 
 
You will be given booklets to complete for this study. This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer. Your answers help us to better 
understand how the treatment you are receiving is affecting the way you feel.  
1. You are being asked to complete a questionnaire booklet for this study. This booklet must be 
completed at the end of each week, prior to the start of another week of treatment.  
2. This booklet contains the following questionnaire(s):  
a. EORTC QLQ-CIPN20 Instrument 
b. Patient Global Impression of Change 
c. Chemotherapy Induced Peripheral Neuropathy Assessment Tool 
d. Symptom Experience Diary – During Treatment 
e. Peripheral Neuropathy Question 
f. Cognitive Functioning Assessment 
3. Directions on how to complete each set of questions are written at the top of the page.  
4. You will be given the nurse’s or study coordinator’s name and telephone number. You can 
call any time with any concerns or questions.  
5. Please complete the booklet and return it, by mail, to your study staff weekly. Please use the 
self-addressed and stamped envelopes provided with the questionnaires. It is very important 
that you return the booklet to us.  
 
Thank you for taking the time to help us. 
 

 
49 
 
Appendix II: EORTC QLQ-CIPN20 Instrument 
 

 
50 
 

 
51 
 
Appendix III: Patient Global Impression of Change 
 
1.  Since starting this study, my overall quality of life is: (please circle one) 
 
-3 
-2 
-1 
0 
+1 
+2 
+3 
 very much moderately 
a little 
about the 
a little 
moderately very much 
 
worse 
worse 
worse 
same 
better 
better 
better 
 
 
2.  Since starting this study, the numbness, tingling or pain in my hands and/or feet is: (please 
circle one) 
 
-3 
-2 
-1 
0 
+1 
+2 
+3 
 very much moderately 
a little 
about the 
a little 
moderately very much 
 
worse 
worse 
worse 
same 
better 
better 
better 
 
3. Would you recommend this therapy, to try to prevent or treat neuropathy, to other 
patients with problems similar to yours? 
 
 No 
 
 Yes 
 
 Unsure 
 
Comments: 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
____________________________ 
 
 

 
52 
 
Appendix IV: Chemotherapy Induced Peripheral Neuropathy Assessment Tool (Quantitative 
Items) 
 
 
 
  
 
Over the last week, how much have your neuropathy symptoms 
interfered with: 
 
Not at all                                                         Completely 
Interfering                                                       Interfering
 
Dressing (buttoning, zipping, etc) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Walking      
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Picking up objects 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Holding onto objects 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Driving 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Participating in hobbies or leisure activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Exercising 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Sleeping 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Sexual activity 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Relationships with other people 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Writing 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Usual household chores 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Enjoyment of life 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 

 
53 
 
Appendix V: Symptom Experience Diary –Baseline ONLY 
Note to study staff: Remove the ‘Symptom Experience Diary – Baseline ONLY’ from patient 
questionnaire booklets for Weeks 1-8. Patients will complete the ‘Symptom Experience Diary -during 
treatment’ for Weeks 1-8 following baseline. 
Note to Patient: This form is to be completed only at baseline prior to the start of your study medication. 
If you have started your study medication, please complete the ‘Symptom Experience Diary – during 
treatment’ instead. 
Please circle ONE number for each item that best describes you over the past 7 days.   
 
1.  Over the past week, did you experience nausea and/or vomiting? 
0
1
2
3
4
5
6
7
8
9
10
Not at all   
 
 
 
 
 
 
 
 
As bad as 
it can 
be 
2. Over the past week, did you experience diarrhea? 
0
1
2
3
4
5
6
7
8
9
10
Not at 
all     
 
 
 
 
 
 
 
 
 
As bad 
as it 
can 
be 
3. Over the past week, please rate your quality of life: 
0
1
2
3
4
5
6
7
8
9
10
As bad 
as it can 
be     
 
 
 
 
 
 
 
 
 
As good 
as it can 
be 
 
 
 
 

 
54 
 
Symptom Experience Diary –during treatment  
The following questions should be answered only after you start the study medication.  
 
Please circle ONE number for each item that best describes you over the past 7 days.   
 
1. Over the past week, did you experience nausea and/or vomiting? 
0
1
2
3
4
5
6
7
8
9
10
Not at all   
 
 
 
 
 
 
 
 
As bad as 
it can 
be 
2. Over the past week, did you experience diarrhea? 
0
1
2
3
4
5
6
7
8
9
10
Not at 
all     
 
 
 
 
 
 
 
 
 
As bad 
as it 
can 
be 
3. Over the past week, please rate your quality of life: 
0
1
2
3
4
5
6
7
8
9
10
As bad 
as it can 
be     
 
 
 
 
 
 
 
 
 
As good 
as it can 
be 
 
4. How many doses of the study medication did you miss over the past week? 
0 times 
1-2 times 
3-4 times 
More than 5 times 
 
 
 
 

 
55 
 
Appendix VI: Peripheral Neuropathy Question 
 
How much of a problem has numbness, tingling or pain in your fingers and/or toes been in the past week? 
 
0
1
2
3
4
5
6
7
8
9
10
 
No numbness 
tingling or pain in 
fingers and/or toes 
 
Numbness, tingling or 
pain in fingers and/or 
toes as bad as you can 
imagine
 
Being more specific, how much of a problem has pain in your fingers/hand and/or toes/feet been in the past 
week? 
 
0
1
2
3
4
5
6
7
8
9
10
 
No pain in fingers 
and/or toes 
 
Pain in fingers and/or 
toes as bad as you can 
imagine
 
 
 

 
56 
 
Appendix VII: Cognitive Functioning Assessment 
 
 
1. How much of a problem have you had concentrating on things, in the past week? 
 
0
1
2
3
4
5
6
7
8
9
10
 
No trouble at all 
 Trouble as bad as you 
can imagine
 
 
 
2.   How much of a problem have you had remembering things, in the past week? 
 
0
1
2
3
4
5
6
7
8
9
10
 
No trouble at all 
 Trouble as bad as you 
can imagine
 
 

 
57 
 
Appendix VIII Nurse/CRP Weekly Phone Contact Guide 
 
 
Patient Phone No.__________________ 
Best Dates/Times to call_____________ 
 
FOLLOW UP: 
 
1. Please make an appointment to call the patient at home the end of each study 
week. The purpose of this contact is to remind the patient of dose schedule, 
document compliance, encourage completion of the booklet, and address 
problems. 
 
 
It is important to reinforce completion of weekly questionnaires. 
Regarding potential side effects, please ask about nausea, vomiting 
and diarrhea. In addition, determine whether there are any reportable 
adverse events (Section 9.0). 
 
2. Items to document on the Nurse/CRP Evaluation form in the forms packet include, but 
are not limited to the following: 
 
Date of phone call 
 
Study week 
 
Side effects: 
 Type of side effect, severity and attribution, if applicable 
 
Any changes in medications or other treatments (i.e. behavioral, diet, etc.) 
 
Has the participant taken the proper amount of study 
medication each day? Choose one:  
 Always (6-7 doses out of 7 for once daily dosing; 
11-14 doses out of 14 for twice daily dosing) __   
,  
 Usually (3-5 doses out of 7 for once daily dosing; 
5-10 doses out of 14 for twice daily dosing) __  
,  
 Rarely (1-2 doses out of 7 for once daily dosing; 
1-4 doses out of 14 for twice daily dosing) __  
, or  
 Never (0 doses taken)   
 
 
Questions/Comments 
 
3. Reinforce compliance with study medication. 
 
4. Ask about use of other cannabinoid products such as CBD and/or THC, noting that they are not 
supposed to be taking them.  If they are, then document and state/suggest that they stop such 
agents. If patient agrees to discontinue, they may remain on active study treatment. If they decline 
to discontinue the cannabinoid, they will be taken off study.  
 
5. Reinforce completion of questionnaires and request return of them. NOTE: If patient decides to 
stop study before Week 8, ask the patient to fill out the questionnaires up to that point at the end 
of the booklet and return in the envelope provided. 

 
58 
 
Appendix IX:  Nurse/study assistant phone call at months 6 and 12. 
 
 
Patient Phone No.__________________ 
 
FOLLOW UP: 
 
1. Please call the patient at home at 6 and 12 months. 
 
 
2. Ask about neuropathy status and what medications that the patient might be taking for 
CIPN: 
 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
3. Ask about whether they have had any recurrent cancer problems: 
 
 
☐Yes 
☐ No 
 
 
If Yes, please describe: 
_____________________________________________________________________________________
_____________________________________________________________________________________