Clinical trial NCT03705832
Conditions: Asthma
Keywords: Ginger Dietary supplement
Sponsor: Emily DiMango, MD
Start date: 2019-08-22; Completion date: 2021-02-28
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double blind, placebo controlled study to study whether there are potential benefits of consuming ginger by individuals with asthma.

Detailed description:
Presently an estimated 25.9 million Americans suffer from asthma and over half have at least one asthma attack per year. Recent studies found that 60% of moderate asthmatics and 70% of severe asthmatics report using complementary and alternative medicine (CAM) to self-treat their asthma symptoms.The exact mechanism of action of these agents is unclear but may involve attenuation of allergic response, anti-inflammatory and antioxidant effects, and/or direct effects on airway smooth muscle which are responsible for airway narrowing in asthma.

Studies done in mouse models of asthma and directly on airway smooth muscle cells demonstrate that ginger blocks one of the critical inflammatory pathways in asthma and thus leads to reduced airway inflammation and relaxation of airway smooth muscle. Clinical trials with chronic oral ginger therapy in humans have demonstrated safe consumption of 2 grams per day for 28 days with demonstrated anti-inflammatory effects in colon cancer and inflammatory bowel diseases. Thus, the investigators hypothesize that oral ginger at a dose of 2 grams per day will reduce airway inflammation and will reduce serum levels of asthma related inflammatory markers.

Arms: arm 1: Subjects assigned to the intervention will receive 2 grams daily of Ginger Extract for 56 days. arm 2: Subjects assigned to the placebo group will receive a matching placebo for 56 days.
Interventions: intervention 1: Ginger Extract intervention 2: Placebo
Intervention descriptions: intervention 1: 2gm Capsule of Ginger extract intervention 2: Matching Placebo

Protocol documents:
Prot_SAP_001.pdf: 
Study Product Guidelines and Considerations 
1 of 38 
Version 1.5 
 
 
22 July 2019 
Clinical Intervention Study 
Protocol Template 
 
 
 
 
 
 
  


Study Product Guidelines and Considerations 
2 of 38 
Version 1.5 
 
 
22July 2019 
FULL PROTOCOL TITLE 
Ginger’s therapeutic potential in Asthma 
Study Chairman or Principal Investigator: 
Emily DiMango, MD, Professor of Medicine, Department of Medicine 
and 
Charles W. Emala, MS, MD, Professor of Anesthesiology, Department of Anesthesiology, 
Vagelos College of Physicians and Surgeons, Columbia University 
 
Supported by:  
The National Center for Complementary and Integrative Health 
1R61AT009989-01 
Study Intervention Provided by: 
Atrium Innovations (Pure Encapsulations) 
Sponsor of IND (IDE): 
Emily DiMango, MD IND# 126513 
 
 
 
NCT03705832 


Study Product Guidelines and Considerations 
3 of 38 
Version 1.5 
 
 
22July 2019 
 


Study Product Guidelines and Considerations 
4 of 38 
Version 1.5 
 
 
22July 2019 
Tool Revision History 
Version Number: 1.1 
Version Date: February 6, 2019  
Summary of Revisions Made: None (Original Version) 
Version Number: 1.2 
Version Date: April 2, 2019 
Summary of Revisions Made: An explanation of the randomization has been added and the 
randomization code will now be held by an independent statistician as opposed to the research 
pharmacy as suggested by the NCCIH review.  We have added the physical locations of where 
patients will be studied and added locations where blood samples will be analyzed.  We have 
clarified that a ‘per protocol’ analysis will be used and have defined how subjects will be defined 
to be compliant with the protocol.  Finally we have made additional minor edits to the protocol to 
respond to ever other comment from NCCIH. 
Version Number: 1.3 
Version Date: April 24, 2019 
Summary of Revisions Made: update 1. Page 8, “Design and Outcomes”, this statement has 
been added: “The eight subjects will be selected through voluntary participation. The option will 
be provided to all subjects who sign the consent. Once there have been 4 subjects in Group A 
and 4 subjects in Group B selected, there will no longer by any additional subjects accepted to 
join the PK study.” 
Update 2. p33, section 9.3 This section is changed to state: “All randomized subjects will be 
included in the primary analysis, analyzed based on intention-to-treat. In addition, a secondary 
analysis based on a per protocol will be conducted. Per protocol analysis will exclude patients 
who missed 30% or more of their assigned treatment.  Please refer to section 5.4 for the 
equation to calculate compliance.” 
Version Number: 1.4 
Version Date: May 7, 2019 
Summary of Revisions Made: Section 4.1.  We have combined elements of inclusion criteria into 
fewer statements and we have responded to the reviewer’s comment in the margin.  As 
requested, we have moved visits 1 and 2 from section 6.2.4 to section 6.2.1.  This created some 
redundancy of statements in section 6.2.1. which has been edited in an attempt to remove the 
redundancy.  
Version Number: 1.5 
Version Date: July 22, 2019 
Summary of Revisions Made: In response to Westat SIV the following changes were made.  
Redundancies were removed from section 4.2 that were already accounted for in Section 4.1.  
Sections 4.1 and 4.2 were then copied into section 6.2 for consistent listing of 
inclusion/exclusion. In section 10.3.4 we added a deviation for study subjects consuming less 
than 70% of the study drug.  In sections 6.2.4 we corrected the dates for the follow up phone 
call for visit 4a.  We have combined elements of inclusion criteria into fewer statements and we 
have responded to the reviewer’s comment in the margin.  As requested, we have moved visits 
1 and 2 from section 6.2.4 to section 6.2.1.  This created some redundancy of statements in 
section 6.2.1. which has been edited in an attempt to remove the redundancy.  
 


Study Product Guidelines and Considerations 
5 of 38 
Version 1.5 
 
 
22July 2019 
 


Study Product Guidelines and Considerations 
6 of 38 
Version 1.5 
 
 
22July 2019 
TABLE OF CONTENTS 
Page 
Clinical Intervention Study Protocol Template ......................................................................... 1 
FULL PROTOCOL TITLE ......................................................................................................... 2 
Tool Revision History ................................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................. 6 
STUDY TEAM ROSTER........................................................................................................... 7 
PARTICIPATING STUDY SITES ............................................................................................ 7 
PRÉCIS ....................................................................................................................................... 7 
1. STUDY OBJECTIVES ............................................................................................................. 9 
1.1 
Primary Objective ........................................................................................................... 9 
1.2 
Secondary Objectives...................................................................................................... 9 
2. BACKGROUND AND RATIONALE .................................................................................. 11 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 11 
2.2 
Study Rationale ............................................................................................................. 11 
3. STUDY DESIGN ..................................................................................................................... 12 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 15 
4.1 
Inclusion Criteria .......................................................................................................... 15 
4.2 
Exclusion Criteria ......................................................................................................... 16 
4.3 
Study Enrollment Procedures ....................................................................................... 16 
5. STUDY INTERVENTIONS .................................................................................................. 17 
5.1 
Interventions, Administration, and Duration ................................................................ 17 
5.2 
Handling of Study Interventions ................................................................................... 18 
5.3 
Concomitant Interventions ............................................................................................ 18 
5.3.1 Allowed Interventions ............................................................................................... 18 
5.3.2 Required Interventions .............................................................................................. 16 
5.3.3 Prohibited Interventions ............................................................................................ 16 
5.4 
Adherence Assessment ................................................................................................. 17 
6. STUDY PROCEDURES ........................................................................................................ 18 
6.1 
Schedule of Evaluations ................................................................................................ 18 
6.2 
Description of Evaluations ............................................................................................ 19 
6.2.1 Screening Evaluation ................................................................................................ 24 
6.2.2 Enrollment, Baseline, and/or Randomization ........................................................... 25 
6.2.3 Blinding..................................................................................................................... 26 
6.2.4 Followup Visits ......................................................................................................... 26 


Study Product Guidelines and Considerations 
7 of 38 
Version 1.5 
 
 
22July 2019 
6.2.5 Completion/Final Evaluation .................................................................................... 28 
7. SAFETY ASSESSMENTS ..................................................................................................... 28 
7.1 
Specification of Safety Parameters ............................................................................... 27 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 27 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 28 
7.4 
Reporting Procedures .................................................................................................... 28 
7.5 
Followup for Adverse Events ....................................................................................... 28 
7.6 
Safety Monitoring ......................................................................................................... 29 
8. INTERVENTION DISCONTINUATION ........................................................................... 29 
9. STATISTICAL CONSIDERATIONS .................................................................................. 31 
9.1 
General Design Issues ................................................................................................... 31 
9.2 
Sample Size and Randomization .................................................................................. 32 
Treatment Assignment Procedures ....................................................................................... 32 
9.3  
Definition of Populations .............................................................................................. 33 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 33 
9.5 
Outcomes ...................................................................................................................... 33 
9.5.1 Primary Outcome ...................................................................................................... 33 
9.5.2 Secondary Outcomes ................................................................................................ 33 
9.6 
Data Analyses ............................................................................................................... 33 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 34 
10.1 
Data Collection Forms .................................................................................................. 34 
10.2 
Data Management ......................................................................................................... 34 
10.3 
Quality Assurance ......................................................................................................... 34 
10.3.1 
Training ................................................................................................................. 34 
10.3.2 
Quality Control Committee................................................................................... 34 
10.3.3 
Metrics .................................................................................................................. 34 
10.3.4 
Protocol Deviations ............................................................................................... 35 
10.3.5 
Monitoring ............................................................................................................ 35 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 36 
11.1 
Institutional Review Board (IRB) Review .................................................................... 36 
11.2 
Informed Consent Forms .............................................................................................. 36 
11.3 
Participant Confidentiality ............................................................................................ 36 
11.4 
Study Discontinuation ................................................................................................... 36 
12. COMMITTEES..................................................................................................................... 36 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 37 


Study Product Guidelines and Considerations 
8 of 38 
Version 1.5 
 
 
22July 2019 
14. REFERENCES ...................................................................................................................... 37 
15. SUPPLEMENTS/APPENDICES ........................................................................................ 38 
 


Study Product Guidelines and Considerations 
9 of 38 
Version 1.5 
 
 
22July 2019 
STUDY TEAM ROSTER  
Emily DiMango, MD (co-PI) email: ead3@cumc.columbia.edu phone: 212-305-0631 fax: 212-342-4784 
Charles W. Emala, MS, MD (co-PI) email: cwe5@cumc.columbia.edu, phone: 212-305-8360 
Amanda Kramer, BS (clinical research coordinator) email: ark2187@cumc.columbia.edu phone: 212-
305-46754765 
 
Eosinophil counts: Center for Advanced Laboratory Medicine (CALM) lab in the Department of 
Pathology at Columbia University, 622 West 168th St. PH 7-200, New York, NY 10032 
 
Sample Storage/Cytokine & Biomarker Analyses: The Laboratory of Charles Emala, MD, Department of 
Anesthesiology, 650 West 168th, Black Building Room 713, New York, NY 10032. 
 
Metabolite and pharmacokinetic Analyses: The Laboratory of Shengmin Sang, PhD, Suite 4222, UNC 
Nutrition Research Building, NCRC, 500 Laureate Way, Kannapolis, NC 28081 
 
PARTICIPATING STUDY SITES 
Columbia University Medical Center, The Johns Edsall-John Wood Asthma Center 
PRÉCIS  
Study Title  
Ginger’s therapeutic potential in asthma 
Objectives  
The primary endpoints are the improved tolerance to the bronchoconstrictive effect (reduced airway 
hyperresponsiveness) of inhaled methacholine  (methacholine PD20) or a reduction in exhaled nitric oxide. 
The secondary endpoints are a reduction in markers of asthmatic lung inflammation; specifically serum 
cytokines, eosinophilia, and establishing pharmacokinetic parameters of biologically active components 
of ginger in adult asthmatics. 
 
Design and Outcomes   
A placebo controlled, double blind, randomized clinical pilot study of mild to severe asthmatics treated in 
a 1:1 ratio with oral ginger 1 gm twice per day or matching placebo.  This will occur in the Columbia 
University Medical Center, The Johns Edsall-John Wood Asthma Center Outpatient Unit, 622 West 168th 
Street, PH 859, New York, NY 10032. 
 
Screening/Run-In PeriodAdults 18 and older, with physician diagnosed mild to severe persistent asthma 
will be screened.  After reviewing and signing informed consent, subjects that fulfill inclusion and 
exclusion criteria will be invited to participate. 
 
Day 0/Visit 1: Screening Visit: review of medical history, recording of medication use, physical exam by 
study MD or NP, scoring on ACT and basic spirometry before and after bronchodilator.   Subjects will 
then be asked to continue their usual asthma medications for the 14-21 day run-in period.  
 
Day 14-21/Visit 2: Subjects will be asked to withhold appropriate medications (long  acting 
bronchodilator for 36 hours, short acting bronchodilator for 6 hours). Women of child bearing potential 
will have a urine pregnancy test checked. Checklist for methacholine will be reviewed with patient. If 
ACT remains ≤ 19 and FEV1> 60% predicted, subjects will undergo methacholine bronchoprovocation 
testing which involves inhaling increasing concentrations of nebulized methacholine until the measured 
FEV1 decreases by 20% of the initial value measured after diluent inhalation, defined as the methacholine 
PD20. If ACT is > 19, consistent with good asthma control, subjects will be terminated from the study. 
 


Study Product Guidelines and Considerations 
10 of 38 
Version 1.5 
 
 
22July 2019 
 
Day 15-23 (1-2 days following V2)/Visit 3 Randomization Visit: 
If ACT remains ≤ 19, subjects will be randomized into 2 treatment groups; oral ginger (1g twice per day: 
Pure Encapsulations™) or matching placebo (FDA IND in place: #126513).  Ratio of randomization will 
be 1:1. An independent statistican will generate the randomization codes and allocations. The blinded 
study coordinator will retrieve the randomization allocation for each subject  through RedCap. RedCap is 
an institutionally available automated system for randomization; the independent statistician  will have 
direct oversight over the process. The blinded study team will not have access to the randomization codes.  
 
At the randomization visit, women of child bearing potential will have a negative pregnancy test 
confirmed, subjects will be asked to complete an ACT to assess asthma control and a validated asthma 
quality of life questionnaire (Juniper mini AQLQ). Fractional excretion of nitric oxide (FeNO) will be 
measured using a Circassia Niox Vero machine with disposable filters. Pre-dose basic spirometry will be 
performed. 10ml of blood will be collected for measurement of baseline cytokines, biomarkers and blood 
eosinophil count. Subjects will be given their first dose of study drug and post-dose spirometry will be 
repeated one hour later.  
 
A total of eight subjects will undergo pharmacokinetic (PK) measurements of the key metabolites of 
active ginger components. For those patients, an additional 35 ml of blood will be collected over an 
additional 7 times points (pre-dose, 0.5 hour,1 hour,2 hour,3 hour, 4 hour, and 8 hour). The eight subjects 
will be selected through voluntary participation. The option will be provided to all subjects who sign the 
consent. Once there have been 4 subjects in Group A and 4 subjects in Group B selected, there will no 
longer by any additional subjects accepted to join the PK study.  
 
Day 43-50/Visit 4:. Subjects will be asked to withhold morning dose of the study drug the day of the 
study visit.  Women of child bearing potential will have a negative pregnancy test confirmed. Subjects 
will be asked to complete an ACT to assess asthma control and a validated asthma quality of life 
questionnaire (Juniper mini AQLQ). FeNO will be measured using a Circassia Niox Vero machine with 
disposable filters.  Basic spirometry will be performed, Methacholine test will be performed if subject 
meets safety criteria (FEV1>1.5L or 60% predicted). 10ml of blood will be collected for measurement of 
cytokines, biomarkers and blood eosinophil count. For those patients in PK group, an additional 35 ml of 
blood will be collected over an additional 7 times points (pre-dose, 0.5 hour,1 hour,2 hour,3 hour, 4 hour, 
and 8 hour).  Study drug will be administered in the clinic after the pre-dose PK blood draw. 
 
Unused study medication will be collected and pill count will be recorded.  
 
Day 71-78/Visit 5: Subjects will be asked to withhold morning dose of the study drug the day of the study 
visit.  Women of child bearing potential will have a negative pregnancy test confirmed. Subjects will be 
asked to complete an ACT to assess asthma control and a validated asthma quality of life questionnaire 
(Juniper mini AQLQ). FeNO will be measured using a Circassia Niox Vero machine with disposable 
filters.  Basic spirometry will be performed. Methacholine hyperresponsiveness will be measured if 
subject meets safety criteria (FEV1 > 1.5L or  >60% predicted).  10ml of blood will be collected for 
measurement of cytokines, biomarkers and blood eosinophil count. For those patients in PK group, an 
additional 35 ml of blood will be collected over an additional 7 times points (pre-dose,0.5 hour,1 hour,2 
hour,3 hour, 4 hour, and 8 hour).  Unused study medication will be collected and pill count will be 
recorded. Study drug will be administered in the clinic after the pre-dose PK blood draw. 
 
 
Sample Size and Population  
Adults 18 and older, with physician diagnosed mild to severe persistent asthma will be screened.  36 
participants will be randomized equally into two arms (18 per group); 1 gram of oral ginger extract twice 
a day for 28 days or matching placebo. Our sample size analysis requires 16 participant per group and 
with an anticipated 10% attrition rate, we will enroll 18/group. 
Randomization will not be stratified in this pilot study. 


Study Product Guidelines and Considerations 
11 of 38 
Version 1.5 
 
 
22July 2019 
The NIH National Asthma Education and Prevention Program (NAEPP) Guidelines for assessing asthma 
severity will be used by the PI to grade severity of asthma.1 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
The primary endpoints are a clinically significant improvement in tolerance to inhaled methacholine 
(PD20) or a clinically significant decrease in exhaled nitric oxide.  A clinically significant increase in 
tolerance to inhaled methacholine is defined as a 0.7 increase in the doubling dose for inhaled 
methacholine from the subjects baseline.  A clinically significant decrease in exhaled nitric oxide is 
defined as a 20% decrease in subjects starting at a baseline of >50 ppb or a decrease of 10 ppb for 
subjects starting at a baseline of <50 ppb.  
1.2 
Secondary Objectives 
a. To determine if oral daily ginger extract intake; 
1. increases forced expiratory volume in one second (FEV1) by 100ml. 
2. decreases blood eosinophilia 
3. decreases asthma-associated cytokines in serum 
b. Establish pharmacokinetic parameters of biologically active components of ginger in adult asthmatics.  
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
The Centers for Disease Prevention and Control report that 9% of Americans have asthma which 
accounted for 1.8 million emergency room visits and 0.5 million hospitalizations in 2011 with a projected 
cost of $56 billion.2 Asthma is a chronic inflammatory disorder of the airways characterized by 
bronchoconstriction and airway inflammation marked by airway hyperresponsiveness.  Current asthma 
therapies include short- and long-acting β-agonists to combat bronchoconstriction and inhaled 
corticosteroids (ICS) to reduce airway inflammation. These medications have important adverse effects, 
are not suitable for some patients, and have poor adherence.3   There are emerging targeted biologic 
therapies, especially directed against the Th2-high endotype of asthma, but these therapies are aimed at 
patients with severe asthma, are expensive, and do not address the multiple endotypes of asthma. 
Consequently, many Americans have increasingly turned towards complementary and alternative 
medicines for treating asthma.  
 
Recent studies found that 60% of moderate asthmatics and 70% of severe asthmatics report using 
complementary and alternative (CAM) therapies to self-treat their asthma symptoms.4  Natural plant 
products in the forms of teas, topical ointments, and dietary supplements have been used for the relief of 
respiratory ailments including cough and bronchospasm.5 Of the many types of CAM therapies chosen by 
asthmatics, as many as 40% of asthmatics use herbal therapies to self-treat their asthma symptoms.4 The 
exact mechanism of action of these agents is unclear but may involve attenuation of the allergic cascade 
through blockade of IgE mediated inflammation, anti-inflammatory and antioxidant effects, and/or direct 
effects on acutely relaxing human airway smooth muscle (ASM).  
2.2 
Study Rationale 
Recently we demonstrated that purified components of ginger (6-shogaol, 6-gingerol, 8-gingerol) acutely 
relaxed human airway smooth muscle (ASM) in vitro6 and our newest preliminary data shows that 
specific human metabolites of these components have potent ASM relaxing properties. Additionally, we 
have preliminary data showing that ginger components reduced lung inflammation in a mouse model of 
asthma. We demonstrated that the cellular mechanism by which ASM relaxation occurs is via inhibition 
of phospholipase C (PLC) a pivotal enzyme that mediates smooth muscle contraction as well as cytokine 
release from immune cells and airway structural cells.6 Thus, natural compounds that inhibit PLC can 


Study Product Guidelines and Considerations 
12 of 38 
Version 1.5 
 
 
22July 2019 
target two key features of the pathophysiology of asthma; smooth muscle constriction and cytokine 
release. It is not possible to measure PLC activity directly in live human subjects, but it is possible to 
directly measure the functional effect of PLC inhibition; improved tolerance for inhaled methacholine and 
reduced inflammation which will be the key biological signatures measured in this 2 month clinical study 
of oral ginger in asthmatics. We contend that this proposal is highly responsive to the goals of this 
program as it (1) studies a natural product in a disease commonly encountered in primary care practice; 
(2) tests a natural botanical substance widely used as a dietary supplement for which sufficient early stage 
safety and mechanistic data justifies further clinical testing; (3) measures the bioavailability of the natural 
product and its major human metabolites; and (4) demonstrates primary biological signatures in patients. 
  
Ginger is widely used as an over-the-counter oral dietary supplement. The formulation and amount of 
ginger used in this study (2g per day; Pure Encapsulations®) has been chemically characterized by HPLC 
and has been administered to patients at the oral amount (2 grams) for 28 days in multiple human studies 
measuring inflammatory mediators in colonic mucosal biopsies.  We chose this formulation and dose 
based on its history of excellent tolerance in previous human studies.  We chose to divide the 2g dose into 
1g twice a day dosing to minimize the chance of gastrointestinal side effects while limiting the burden on 
subject dosing to twice a day to increase retention and compliance within the study.  We have also 
demonstrated in pre-clinical studies in a mouse model of asthma that this dose reduces asthma-associated 
lung inflammation.  
 
The incidence of side effects in a 28 day trials of 30 individuals were not significantly different in placebo 
versus ginger and no adverse events were greater than the NCI Common Toxicity Criteria Grade 1. In a 
second study of 27 individuals, no adverse event greater than NCI Common Toxicity Criteria Grade 1 
was reported (no placebo comparison) and the leading complaints were gastrointestinal symptoms of 
eructation, heartburn or indigestion.7 In a third study of 20 patients consuming the same formulation in 
the same amount for the same duration (2g, Pure Formulations, 28 days) no statistically significant 
increase in adverse events occurred compared to placebo, no toxicities were greater than the NCI 
Common Toxicity Criteria Grade 1 and included bloating, nausea and heartburn. 
 
There have been small numbers of studies reporting on possible  inhibition of platelet aggregation by 
ginger. Ginger has been shown an in vitro study to inhibit platelet aggregation with a potency similar to 
that of aspirin and in another study of human volunteers, to have a syngergistic effect with nifedipine in 
platelet aggregation.8-10 A single case report has been published demonstrating epistaxis in a women who 
was being treated with Coumadin who subsequently started taking ginger.11 Subjects taking anti-
coagulation will be excluded from participation, though subjects taking aspirin alone will be included in 
the study since there have been no studies or reports of increased bleeding risk with aspirin and ginger 
combined.  
3. STUDY DESIGN 
A placebo controlled, double blind, randomized clinical pilot study of mild to severe asthmatics treated in 
a 1:1 ratio with oral ginger 1 gm twice per day or matching placebo.   
18 subjects will be assigned to each of two arms (ginger vs. placebo).  This is defined by a power analysis 
requiring 16 subjects per arm and a 10% projected attrition rate.  Subjects will be evaluated 5 times 
during the study, at screening, baseline methacholine testing, at the initial randomization visit and at days 
28 and 56 while taking ginger or placebo.  
 
The primary outcomes will be the improved tolerance to the bronchoconstrictive effect (reduced airway 
hyperresponsiveness) of inhaled methacholine  (methacholine PD20) or a reduction in exhaled nitric oxide. 
Secondary outcomes will include an improvement in baseline FEV1 of 100ml, a reduction in eosinophilia 
or a reduction in asthma associated serum cytokines.  An additional secondary outcome will be defining 
the pharmacokinetic profile of active components of ginger in adult asthmatics. 


Study Product Guidelines and Considerations 
13 of 38 
Version 1.5 
 
 
22July 2019 
 
 
Outpatient; The John Edsall-John Wood Asthma Center at the Columbia University Medical Center 
Individual enrollment: 78 +/- 7 days. Enrollment period 12 months,   Entire trial (first subject screened to 
last patient completed): 20 months. 
 
Screening/Run-In Period 
 
Adults 18 and older, with physician diagnosed mild to severe persistent asthma will be screened.  After 
reviewing and signing informed consent, subjects that fulfill inclusion and exclusion criteria will be 
invited to participate. 
 
Day 0/Visit 1: Screening Visit: review of medical history, recording of medication use, physical exam by 
study MD or NP, scoring on ACT and basic spirometry before and after bronchodilator.   Subjects will 
then be asked to continue their usual asthma medications for the 14-21 day run-in period.  
 
Day 14-21/Visit 2: Subjects will be asked to withhold appropriate short and long acting bronchodilators 
for the appropriate period. Women of child bearing potential will have a urine pregnancy test checked. 
Checklist for methacholine will be reviewed with patient. If ACT remains ≤ 19 and FEV1> 60% 
predicted, subjects will undergo methacholine bronchoprovocation testing which involves inhaling 
increasing concentrations of nebulized methacholine until the measured FEV1 decreases by 20% of the 
initial value measured after diluent inhalation, defined as the methacholine PD20. If ACT is > 19, 
consistent with good asthma control, subjects will be terminated from the study. 
 
Day 15-23 (1-2 days following V2)/Visit 3 Randomization Visit: 
If ACT remains ≤ 19, subjects will be randomized into one of two  treatment groups; oral ginger (1g twice 
per day: Pure Encapsulations™) or matching placebo (FDA IND in place: #126513).  Ratio of 
randomization will be 1:1. 
 
At the randomization visitwomen of child bearing potential will have a negative pregnancy test 
confirmed, subjects will be asked to complete an ACT to assess asthma control and a validated asthma 
quality of life questionnaire (Juniper mini AQLQ). Fractional excretion of nitric oxide (FeNO) will be 
measured using a Circassia Niox Vero machine with disposable filters. Pre-dose basic spirometry will be 
performed. 10ml of blood will be collected for measurement of baseline cytokines, biomarkers and blood 
eosinophil count. Subjects will be given their first dose of study drug and post-dose spirometry will be 
repeated one hour later.  
 
Grant 
phase 
Spec. 
Aim 
Primary 
outcome 
Clinically 
Significant 
Change [ref] 
Means ± S.D; 
examples from 
literature [ref] 
(units) 
Sample 
Size 
\group 
# of groups 
Sample 
size 
require
d 
Sample Size 
required 
with 10% 
attrition 
R61 
1 
Mch 
PD20 
doubling 
dose 
Increase of  
0.7 in Mch 
doubling 
dose12 
1.07 ± 0.6 
1.73 ± 0.6 
(Mch doubling 
dose)12 
14 
2 
2g/day 
ginger 
placebo 
28 
32 
2 
Exhaled 
nitric 
oxide 
20% decr for 
>50 ppb or 
decr of 
10ppb for 
<50ppb13 
74 ± 37 
37 ± 34 
(ppb)14 
16 
2 
2g/day 
ginger 
placebo 
32 
36 for aims 
1&2 


Study Product Guidelines and Considerations 
14 of 38 
Version 1.5 
 
 
22July 2019 
A subset of subjects (4 males and 4 females) will undergo pharmacokinetic (PK) measurements of the key 
metabolites of active ginger components. For those patients, an additional 35 ml of blood will be collected 
over an additional 7 times points (pre-dose, 0.5 hour,1 hour,2 hour,3 hour, 4 hour, and 8 hour). 
 
Day 43-50/Visit 4:. Subjects will be asked to withhold morning dose of the study drug the day of the 
study visit.  Women of child bearing potential will have a negative urine pregnancy test confirmed. 
Subjects will be asked to complete an ACT to assess asthma control and a validated asthma quality of life 
questionnaire (Juniper mini AQLQ). FeNO will be measured using a Circassia Niox Vero machine with 
disposable filters.  Basic spirometry will be performed, Methacholine test will be performed if subject 
meets safety criteria (FEV1>1.5L or 60% predicted). 10ml of blood will be collected for measurement of 
cytokines, biomarkers and blood eosinophil count. For those patients in PK group, an additional 35 ml of 
blood will be collected over an additional 7 times points (pre-dose, 0.5 hour,1 hour,2 hour,3 hour, 4 hour, 
and 8 hour).  Study drug will be administered in the clinic after the pre-dose PK blood draw. 
 
Unused study medication will be collected and pill count will be recorded.  
 
Day 71-78/Visit 5: Subjects will be asked to withhold morning dose of the study drug the day of the study 
visit.  Women of child bearing potential will have a negative pregnancy test confirmed. Subjects will be 
asked to complete an ACT to assess asthma control and a validated asthma quality of life questionnaire 
(Juniper mini AQLQ). FeNO will be measured using a Circassia Niox Vero machine with disposable 
filters.  Basic spirometry will be performed. Methacholine hyperresponsiveness will be measured if 
subject meets safety criteria (FEV1 > 1.5L or  >60% predicted).  10ml of blood will be collected for 
measurement of cytokines, biomarkers and blood eosinophil count. For those patients in PK group, an 
additional 35 ml of blood will be collected over an additional 7 times points (pre-dose,0.5 hour,1 hour,2 
hour,3 hour, 4 hour, and 8 hour).  Unused study medication will be collected and pill count will be 
recorded. Study drug will be administered in the clinic after the pre-dose PK blood draw. 
 
Randomization is a process that assigns participants/subjects by chance (rather than by choice) into 
specific groups, typically for clinical research and clinical trials. An independent statistican will generate 
the randomization codes and allocations. The blinded study coordinator will retrieve the randomization 
allocation through RedCap at the time of the randomization visit.. RedCap is an institutionally available 
automated system for randomization; the independent statistician will have direct oversight over the 
process. The blinded study team will not have access to the randomization codes.  In this module, 
randomization model is defined as Drug A and Drug B in a 1:1 ratio. Drug A and Drug B may refer to 
placebo or active drug, however they are left coded as such to ensure blinding. The module creates a 
template allocation table, which the user uses to structure the randomization table to be imported. The 
module also monitors the overall allocation progress and assignment of randomized subjects to ensure 
equal proportions of active drug and placebo.  Only one site member will be allowed randomization 
privileges, but the site will confirm, and lock the specific data field to ensure that no data is altered after 
randomization. There is no stratification, and there are no variable block sizes. 
 
All evaluations and blood draws will be completed at a single site at a single center, the 
outpatient clinic of The John Edsall-John Wood Asthma Center at the Columbia University 
Medical Center.  Blood eosinophils will be measured by the Center for Advanced Laboratory 
Medicine (CALM) with the Department of Pathology and Cell Biology at Columbia University 
Medical Center.  Plasma cytokines will be measured by multiplex array in the laboratory of 
Charles Emala, at Columbia University and the metabolite measurements within the PK studies 
will be performed by Shengmin Sang, PhD , Suite 4222, UNC Nutrition Research Building, NCRC, 
500 Laureate Way, Kannapolis, NC 28081. 
. 


Study Product Guidelines and Considerations 
15 of 38 
Version 1.5 
 
 
22July 2019 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
1. Adults aged 18 years and above, with mild to severe persistent asthma will be enrolled as defined 
by The NIH National Asthma Education and Prevention Program (NAEPP) Guidelines for 
Assessing Asthma Severity1 (please see table page 9).  Subjects will have asthma which is not 
optimally controlled as defined by Asthma Control Test (ACT) score,  despite the current use of 
inhaled corticosteroids with or without inhaled long-acting beta agonists. 
2. Treatment with inhaled corticosteroids (ICS) +/- long acting β-agonists/long acting muscarinics 
and montelukast;  
3. Physician diagnosed asthma, confirmed by patient history/report, as well as pulmonary function 
test (FEV1 ≥60% of predicted or 1.5 L) and methacholine testing (Baseline methacholine PD20 < 
16 mg/ml if taking ICS   or < 8 mg/ml if not taking ICS at Visit 2) to confirm diagnosis.  
4. Non-smoker (e.g., tobacco, e-cigarette, marijuana) for ≥1 yr.; Nicotine patch or gum is allowed. 
5. ≤10 pack-year smoking history;  
6. Suboptimal control of asthma as determined by a score < 19 or less on the Asthma Control Test 
(ACT) at Screening and Randomization Visits. 
7. Ability to understand the English or Spanish language and to understand the study procedures and 
comply with them for the entire study period. 
8. Females of childbearing potential: Pregnant or lactating; participants of appropriate age will be 
screened with urine pregnancy tests at each visit and cannot participate if pregnant. Participants 
must agree to use effective contraception during the trial. 
9.  
 
Prior Medical Therapy 
Washouts: 
The chart below lists medications/substances that decrease airway hyper-responsiveness and should not 
be taken prior to pulmonary function testing. Withholding times are listed next to the medication. 
Medications/Substances 
Withhold/Washout 
Times before test 
Caffeine, cola drinks, and chocolate
Avoid the day of
Alcohol
4hrs
Short-acting β-agonists in conventional 
inhaled doses (e.g. albuterol 200 μg)                                                                      
6 hrs
Long-acting β-agonists (e.g. salmeterol)
36 hrs
Ipratropium (Atrovent 40 μg)
12 hrs
Long-acting anti-muscarinic agents (e.g. tiotropium)
⩾168 hrs (7days)
Ultra-long-acting β-agonists (i.e. indacaterol, vilanterol, olodaterol) Oral 
theophylline                                          
24-48 hours (2 days) 
Oral theophylline                                          
12-24 Hrs 
 
 


Study Product Guidelines and Considerations 
16 of 38 
Version 1.5 
 
 
22July 2019 
4.2 
Exclusion Criteria 
Subjects with any of the exclusion criteria will be excluded from study participation. 
1. Other major chronic illnesses: Conditions which in the judgment of the study physician would 
interfere with participation in the study, e.g., non-skin cancer, uncontrolled diabetes mellitus, 
coronary artery disease, congestive heart failure, stroke, severe hypertension, renal failure, liver 
disorders, malabsorption disorders, immunodeficiency states, major neuropsychiatric disorder; 
2. Cardiovascular problems: 
a. Myocardial infarction or stroke in last 3 months 
b. Uncontrolled hypertension 
c. Known aortic aneurysm 
3. History of physician diagnosis of chronic bronchitis, emphysema or COPD 
4. Medication use:  
a. Current consumption of ginger supplements 
b. oral corticosteroid use within the past 6 weeks 
c. use of an investigational treatment in the previous 30 days 
d. Use of anti-coagulation such as warfarin, rivaroxaban and similar agents. 
5. Known adverse reaction to ginger or ginger products 
6. Subjects with cancer, other than skin cancer, will be excluded.  
7. Current drug or alcohol use or dependence that, in the opinion of the site investigator, would 
interfere with adherence to study requirements 
8. Inability or unwillingness of individual or legal guardian/representative to give written informed 
consent.  
4.3 
Study Enrollment Procedures  
Participants will be recruited by a variety of methods that have been used previously by the study team. 
These methods may include solicitation in physician offices, clinics, workplaces, and public media 
advertisements. All public advertisements will first be approved by the Institutional Review Board (IRB).  
Potential enrollees will be approached either in person, by telephone or by mail to establish general 
eligibility criteria.  
Documentation of ineligibility and non-participation of eligible candidates will be recorded within a 
screening log.  
 
Potential enrollees will meet with the study Coordinator and local physician co-investigators to review the 
study in a quiet room and will be given as much time as needed to read the consent and ask questions. The 
consents, HIPAA Authorization and all study questionnaires will be available in English and Spanish. If 
they agree to participate,  they will be asked to sign a consent.  A copy of the consent form will be given 
to each participant, and the signed original will be kept in the participant’s research chart.  Only 
participants who are capable of providing their own informed consent will be enrolled. 
 
Randomization is a process that assigns participants/subjects by chance (rather than by choice) into 
specific groups, typically for clinical research and clinical trials. An independent statistican will generate 
the randomization codes and allocations. The blinded study coordinator will retrieve the randomization 
allocation through RedCap. RedCap is an institutionally available automated system for randomization 
and the statistician will have direct oversight over the process. The blinded study team will not have 
access to the randomization codes.  In this module, randomization model is defined as Drug A and Drug 
B in a 1:1 ratio. Drug A and Drug B may refer to placebo or active drug, however they are left coded as 
such to ensure blinding. The module creates a template allocation table, which the user uses to structure 
the randomization table to be imported. The module also monitors the overall allocation progress and 
assignment of randomized subjects to ensure equal proportions of active drug and placebo.  Only one site 


Study Product Guidelines and Considerations 
17 of 38 
Version 1.5 
 
 
22July 2019 
member will be allowed randomization priviledges, but the site will confirm, and lock the specific data 
field to ensure that no data is altered after randomization. There is no stratification, and there are no 
variable block sizes. 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
A 28-day supply of study drug (ginger capsules) or placebo (matching capsules) will be dispensed from 
the Columbia University Medical Center research pharmacy in a blinded fashion and distributed to the 
study subjects by the clinical research coordinator in the asthma clinic.  Patients will take their first dose 
of study drug at the study site during the randomization visit and will then be instructed to take 1g twice a 
day with meals in the outpatient setting.  Patients participating in the pharmacokinetic studies will be told 
to hold their daily dose on subsequent clinic visit dates until timed dosing occurs in the clinic.  
Potential Adverse Events; Ginger is widely used as an over-the-counter dietary supplement. The 
formulation and amount of ginger used in this study (2g per day; Pure Encapsulations®) has been 
chemically characterized by HPLC and has been administered to patients at the oral amount (2 grams) for 
28 days in multiple human studies measuring inflammatory mediators in colonic mucosal biopsies. The 
incidence of side effects in a 28 day trials of 30 individuals were not significantly different in placebo 
versus ginger and no adverse events were greater than the NCI Common Toxicity Criteria Grade 1. In a 
second study of 27 individuals no adverse event greater than NCI Common Toxicity Criteria Grade 1 was 
reported (no placebo comparison) and the leading complaints were gastrointestinal symptoms of 
eructation, heartburn or indigestion.15 In a third study of 20 patients consuming the same formulation in 
the same amount for the same duration (2g, Pure Formulations, 28 days) no statistically significant 
increase in adverse events occurred compared to placebo, no toxicities were greater than the NCI 
Common Toxicity Criteria Grade 1 and included bloating, nausea and heartburn. 
 
There have been small numbers of studies reporting on possible  inhibition of platelet aggregation by 
ginger. Ginger has been shown an in vitro study to inhibit platelet aggregation with a potency similar to 
that of aspirin and in another study of human volunteers, to have a syngergistic effect with nifedipine in 
platelet aggregation.8-10 A single case report has been published demonstrating epistaxis in a women who 
was being treated with Coumadin who subsequently started taking ginger.11 Subjects taking anti-
coagulation will be excluded from participation, though subjects taking aspirin alone will be included in 
the study since there have been no studies or reports of increased bleeding risk with aspirin and ginger 
combined.  
 
Available Supportive Care: A bronchodilator (albuterol/salbuterol) will be available to be administered if 
the participant is uncomfortable from the effects of the methacholine challenge test. A physician or nurse 
practitioner will be available during all methacholine tests. 
 
There is no dose escalation component to this study. 
No modification to the study interventions will be employed without prior review and approval of the 
NCCIH, FDA, IRB and DSMB.  The leading expected complaints associated with oral ginger 
consumption are gastrointestinal symptoms of eructation, heartburn or indigestion.  We will utilize the 
National Cancer Institute Common Toxicity Criteria (CTCAE) Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline:  
 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL.  
Grade 4 Life-threatening consequences; urgent intervention indicated.  


Study Product Guidelines and Considerations 
18 of 38 
Version 1.5 
 
 
22July 2019 
Grade 5 Death related to AE. 
FDA IND approves the administration of this dietary supplement from Pure Encapsulations at a dose of 
2g/day for a duration of 56 days.  No changes in these parameters are anticipated.  
5.2 
Handling of Study Interventions  
The study drug (~500mg capsules) (ginger extract from Pure Encapsulations) and matching placebo have 
been provided to our research pharmacy and packaged (120 capsules/bottle) by the manufacturer.  Each 
bottle is  labeled ‘A’ or ‘B’ and the code is held by the research pharmacy.  Study drug is stored at room 
temperature; temperature logs are maintained by Research Pharmacy.  For distribution to study subjects, 
the clinical research coordinator will obtain the appropriately labeled bottle from the research pharmacy 
on the day of the study visit and distribute to the subject.  Unused study drugs and placebo will be 
destroyed.    
Study intervention accountability records will be the case report source documents that will be stored 
within the study binder and include (1) inclusion/exclusion documentation; (2) medical history; (3) 
concomitant medications; (4) adverse events; (5) methacholine challenge data; (6) individual source 
documents for visits 1-5. 
 
There are no lifestyle/behavioral interventions in this study.  Not applicable.  
The placebo is in an identically appearing capsule as the study compound. Taste of placebo and ginger is 
matched as per manufacturer. 
5.3 
Concomitant Interventions  
Required medications: Inhaled corticosteroids with or without long-acting beta agonists. 
Allowed medications: Long acting anti-muscarinics, montelukast, or other medications not specifically 
excluded. 
Prohibited medications: anti-coagulants such as warfarin, rivaroxaban and similar agents 
5.3.1 Allowed Interventions 
Subjects will continue their usual asthma medications during the study except for the washout periods 
listed in section 4.1.  Patients will continue their inhaled corticosteroids with or without inhaled long 
acting beta agonists and/or long acting anti-muscarinic medications.  Additional asthma medications (e.g. 
montelukast) are also allowed.  Rescue of asthma symptoms with short-acting beta agonists is also 
allowed and if this occurs within a washout period, the study visit will be re-scheduled.  Subjects who are 
not excluded due to the use of anti-coagulants will continue the use of all other prescribed medications. 
5.3.2 Required Interventions 
No other required interventions. 
5.3.3 Prohibited Interventions 
Subjects prescribed anti-coagulants (warfarin, rivaroxaban and similar agents) are excluded from 
participating in the study and are prohibited while the participant is in the study. 
5.4 
Adherence Assessment  
Adherence will be recorded by pill counts at the 28 day and 56 day visit.  Adherence will be defined by at 
least 70% of the capsules consumed. Compliance will be calculated as such: 
Number of doses taken by the subject = Number of pills dispensed – number of pills returned 
Number of doses expected = will be calculcated by the SC based on the date of visit and original date 
dispensed, times the number of pills that should be taken per day 
 


Study Product Guidelines and Considerations 
19 of 38 
Version 1.5 
 
 
22July 2019 
𝐴𝑑ℎ𝑒𝑟𝑒𝑛𝑐𝑒= 100 −൭൬𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑− 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑜𝑠𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 𝑏𝑦 𝑡ℎ𝑒 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑
൰∗100൱ 
 
 
 
 


Study Product Guidelines and Considerations 
20 of 38 
Version 1.5 
 
 
22July 2019 
6. STUDY PROCEDURES  
6.1 
Schedule of Evaluations 
Assessment 
Screening: 
Visit 1  
(Day 1) 
Baseline, 
Enrollment  
Visit 2  
(Day 14-21) 
Study & 
Randomization 
Visit 3  
(Day 15-22) 
Study  Visit  
Visit 4 
(Day 43-50) 
Study Visit 
Visit 5 
(Day 71-78) 
Informed Consent Form   
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Administer Asthma Control Test (ACT) 
X 
X 
X 
X 
X 
Administer QOL questionnaire 
 
 
X 
X 
X 
Administer 2 week recall questionnaire 
 
 
X 
X 
X 
Confirm Medication Washouts 
X 
X 
X 
X 
X 
Medical History  
X 
 
X 
 
 
General Physical Examination 
X 
 
X 
X 
X 
Urine pregnancy test for women of 
childbearing age
X 
 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
Vital Signs 
X 
 
X 
X 
X 
Spirometry 
X 
X 
X 
X 
X 
Post-Bronchodilator Spirometry 
X 
 
 
 
 
Methacholine Bronchoprovocation 
 
X 
 
X 
X 
Administer bronchodilator 
X 
X 
 
X 
X 
Methacholine Recovery challenge 
 
X 
 
X 
X 
GI side effects checklist 
 
 
X 
X 
X 
Measure exhaled nitric oxide 
 
 
X 
X 
X 
Blood draw for cytokines, eosinophilia, 
biomarkers
 
 
X 
X 
X 
Enrollment/Randomization 
 
 
X 
 
 
Pre-dose blood draw for PK subjects 
 
 
X 
X 
X 
Administer dose of study drug 
 
 
X 
X 
X 
Post dose spirometry (1hr) 
 
 
X 
 
 
PK blood draws for selected subjects 
 
 
X 
X 
X 
Dispense drug 
 
 
X 
X 
 
IP Accountability 
 
 
 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
 


Study Product Guidelines and Considerations 
21 of 38 
Version 1.5 
 
 
22July 2019 
6.2 
Description of Evaluations  
Informed Consent Form: If the potential enrollees are interested in participating, they will meet with the 
study Coordinator and local physician co-investigators to review the study and to ask questions. They will 
be asked to sign consent.  A copy of the consent form will be given to each participant, and the signed 
original will be kept in the participant’s research chart.  Only participants who are capable of providing 
their own informed consent will be enrolled.  The consents, HIPAA Authorization and all study 
questionnaires will be available in English and Spanish. 
Demographics: Collection will include age, gender, race, education and zip code.  
 
Asthma Control Test (ACT): Asthma symptom score will be measured with the Asthma Control Test at 
all visits.  This instrument, which has been validated for ages 12-84 years, is a5 question, 4-week recall 
questionnaire that addresses issues of asthma control, symptoms, and nocturnal awakenings. 
 
Juniper mini-Asthma specific quality of life (QOL): Asthma specific quality of life is measured with 
instruments developed and validated by Juniper, Guyatt and colleagues. 
 
Asthma Two Week Recall: The Asthma two week recall (A2WR) was developed to capture the inherent 
intensity of the disease in individuals with asthma. It quantifies severity by combining information about 
impairment, risk, and the amount of medication required to maintain control.  
 
Confirm Medication Washouts: Cessation of medications will be confirmed at study visits as described 
in the table in section 4.1.  If inadequate washouts have not occurred, the study visit will be re-scheduled. 
 
Medical History: Relevant medical history, including history of current disease, other pertinent 
respiratory history, and information regarding underlying diseases will be recorded at the Screening visit 
and confirmed during the randomization visit.   
 
General Physical Exam: A complete physical examination will be performed by either the Investigator or 
a Sub-Investigator as indicated on the Schedule of Events. Complete physical examinations will include a 
minimum of a review of the subject’s general appearance, head, eyes, ears, nose, and throat (HEENT), 
neck, heart, lungs, abdomen, extremities, skin, and general neurological system.  Symptom-oriented or 
brief physical examinations will be performed at time points noted in the Schedule of Events and as 
clinically indicated. New abnormal physical exam findings not present during the follow up visits will be 
recorded as AEs and followed during subsequent visits.  
 
Concurrent Medications/therapies: Will be documented throughout the course of the study. Dose, route, 
unit frequency of administration, and indication for administration and dates of medication will be 
captured.  
 
Urine Pregnancy Test: A urine pregnancy test will be obtained from female subjects who are of 
childbearing age prior to their participation and at every study visit in this study. 
 
Inclusion/Exclusion Criteria:  
Inclusion Criteria:  
Subjects must meet all of the inclusion criteria to participate in this study. 
1. Adults aged 18 years and above, with mild to severe persistent asthma will be enrolled as defined 
by The NIH National Asthma Education and Prevention Program (NAEPP) Guidelines for 
Assessing Asthma Severity1 (please see table page 9).  Subjects will have asthma which is not 
optimally controlled as defined by Asthma Control Test (ACT) score,  despite the current use of 
inhaled corticosteroids with or without inhaled long-acting beta agonists. 
2. Treatment with inhaled corticosteroids (ICS) +/- long acting β-agonists/long acting muscarinics 
and montelukast;  


Study Product Guidelines and Considerations 
22 of 38 
Version 1.5 
 
 
22July 2019 
3. Physician diagnosed asthma, confirmed by patient history/report, as well as pulmonary function 
test (FEV1 ≥60% of predicted or 1.5 L) and methacholine testing (Baseline methacholine PD20 < 
16 mg/ml if taking ICS   or < 8 mg/ml if not taking ICS at Visit 2) to confirm diagnosis.  
4. Non-smoker (e.g., tobacco, e-cigarette, marijuana) for ≥1 yr.; Nicotine patch or gum is allowed. 
5. ≤10 pack-year smoking history;  
6. Suboptimal control of asthma as determined by a score < 19 or less on the Asthma Control Test 
(ACT) at Screening and Randomization Visits. 
7. Ability to understand the English or Spanish language and to understand the study procedures and 
comply with them for the entire study period. 
8. Females of childbearing potential: Pregnant or lactating; participants of appropriate age will be 
screened with urine pregnancy tests at each visit and cannot participate if pregnant. Participants 
must agree to use effective contraception during the trial. 
 
Exclusion Criteria: 
Subjects with any of the exclusion criteria will be excluded from study participation. 
1. Other major chronic illnesses: Conditions which in the judgment of the study physician would 
interfere with participation in the study, e.g., non-skin cancer, uncontrolled diabetes mellitus, 
coronary artery disease, congestive heart failure, stroke, severe hypertension, renal failure, liver 
disorders, malabsorption disorders, immunodeficiency states, major neuropsychiatric disorder; 
2. Cardiovascular problems: 
a. Myocardial infarction or stroke in last 3 months 
b. Uncontrolled hypertension 
c. Known aortic aneurysm 
3. History of physician diagnosis of chronic bronchitis, emphysema or COPD 
4. Medication use:  
d. Current consumption of ginger supplements 
e. oral corticosteroid use within the past 6 weeks 
f. use of an investigational treatment in the previous 30 days 
g. Use of anti-coagulation such as warfarin, rivaroxaban and similar agents. 
5. Known adverse reaction to ginger or ginger products 
6. Subjects with cancer, other than skin cancer, will be excluded.  
7. Current drug or alcohol use or dependence that, in the opinion of the site investigator, would 
interfere with adherence to study requirements 
8. Inability or unwillingness of individual or legal guardian/representative to give written informed 
consent.  
 
Vital Signs: Height, weight, smoking status, number of pack years will be collected at the screening visit. 
Measurement of body temperature, blood pressure, pulse, SpO2 and respirations will be performed after 
resting for 5 minutes at every visit. 
 
Spirometry: Subjects will be asked to perform pulmonary function testing for collection of lung function 
data at each visit. Pulmonary function testing will be performed according to American Thoracic Society 
(ATS) guidelines (2005). Subjects will be tested using the same spirometry equipment at every visit. Up 
to 8 efforts will be performed to obtain 3 acceptable and reproducible test results. The best results from 
the 3 acceptable and reproducible efforts for PFTs will be recorded on the subject’s case report form and a 
copy of the spirometry reports will be retained with the subject’s source documents.   
 
Post-Bronchodilator Spirometry: Will be performed 15 mins after inhalation of 4 puffs of a short acting 
Bronchodilator. 
 


Study Product Guidelines and Considerations 
23 of 38 
Version 1.5 
 
 
22July 2019 
Methacholine Provocation: A methacholine challenge test is a medical test used to assist in the diagnosis 
of asthma. The patient breathes in nebulized methacholine at gradually increasing doubling doses, starting 
with diluent only.  Methacholine provokes bronchoconstriction, or narrowing of the airways via M3 
receptors. The degree of narrowing can then be quantified by spirometry which is performed after 
inhalation of each dose. Once the FEV1 drops by 20% or more from baseline diluent spirometry, the test 
in halted.  
 
Methacholine Recovery Challenge Albuterol will be administered by inhalation (4 puffs) at the end of 
the methacholine provocation test to return the patients FEV1 back to baseline:  
 
GI side effect checklist: Patients will be asked about the frequency and severity of GI symptoms 
including eructation, heartburn, nausea, bloating or indigestion at Visits 3,4 and 5.  
 
Measured Exhaled Nitric Oxide (FeNO): FeNO is widely used as a global measure of lung 
inflammation.  Exhaled breath will be collected from forced expirations using disposable mouthpieces for 
the online exhaled NO (Circassia) procedure described in the American Thoracic Society (ATS) 
guidelines. FeNO levels will be measured at Visits 3,4 and 5.   
 
Blood Draw for Cytokines, eosinophilia, biomarkers: Peripheral venous blood venous blood will be 
collected at Visit 3, 4 and 5 for the measurement eosinophils and cytokines and biomarkers. 8 subjects 
will also have blood collected for pharmacokinetic studies.  Eosinophils counts will be measured in the 
Center for Advanced Laboratory Medicine (CALM) lab in the Department of Pathology at Columbia 
University located at 622 West 168th St. PH 7-200, New York, NY 10032. Multiplex cytokine analyses 
will be performed in the laboratory of Charles Emala, MD, Department of Anesthesiology, 650 West 
168th, Black Building Room 713, New York, NY 10032. 
 
Enrollment/Randomization: Randomization to either ginger capsules or placebo will be done using an 
randomization algorithm within REDCap in a blinded fashion (group A or B). 
 
Pre-Dose blood draw for PK subjects: Study drug should be withheld the day of the study visit for the 
PK subgroup.  Study drug will be administered in the clinic after the pre-dose PK blood draw 
Administer Study Drug: At the randomization visit, subjects will receive 2 capsules of either ginger 
extract (~500mg) or identical appearing placebo based on their randomization group. 
 
Post-Dose Spirometry (1hr): On visit 3, Subjects will repeat spirometry 1 hr after the ingestion of 2 
capsules of ginger extract (~500mg capsules) or two capsules of placebo to determine if there is an acute 
bronchodilatory benefit of ginger.   
 
PK blood draws for PK subjects: Pharmacokinetic (PK) Measurements:  
Subject plasma will be obtained for the measurement of PK measurements at Visit 3, Visit 4, and Visit 5 
from a group of 8 subjects (4 Males & 4 Females). Serum samples will be collected at the following time 
points before and after the oral ingestion of 1g ginger; At Day 1, 28 & 56: Pre Dosing (time 0), Post 
Dosing 0.5, 1, 2,3, 4,& 8 hrs. We will quantify major metabolites of 6-shogaol (i.e. M2, M6, M9, and 
M11) and major metabolites of 6-gingerol (6-gingerdiols). Samples will be aliquoted and stored in such a 
manner that additional metabolites of these ginger components and additional ginger components (8-
shogoal, 10-shogaol, 8-gingerol, 10-gingerol) and their metabolites can be evaluated in future studies. 
Samples will be processed, aliquoted and stored in the research laboratory of Charles Emala (Black 
building room 713;650 West 168th St., New York, NY 10032.  Plasma samples will be shipped on dry ice 
to the laboratory of Shengmin Sang, PhD at Suite 4222, UNC Nutrition Research Building, NCRC, 500 
Laureate Way, Kannapolis, NC 28081. 
 
 


Study Product Guidelines and Considerations 
24 of 38 
Version 1.5 
 
 
22July 2019 
Dispense Drug: Capsules containing ginger extract (~500mg) or placebo will be ingested by the patient at 
a recorded time at the randomization visit to allow for 1hr post-spirometry and PK measurements in 
selected subjects. Drug will also be dispensed at visit 4. 
 
Pill Count: At study visits 4 and 5 pill counts will be recorded to document compliance with the study 
drug or placebo. 
 
Concomitant Medications: All current medications will be recorded including dose and last time taken. 
 
Adverse Events: Definition of adverse event/serious adverse event: An Adverse Event (AE) is any 
unfavorable and unintended symptom, or disease temporally associated with the administration of ginger 
or the clinical testing proposed that may or may not be considered related to the medical treatment or 
procedure. 
Classification of adverse event severity: We will utilize the National Cancer Institute Common Toxicity 
Criteria (CTCAE) Grades 1 through 5 with unique clinical descriptions of severity for each AE based on 
this general guideline:  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL.  
Grade 4 Life-threatening consequences; urgent intervention indicated.  
Grade 5 Death related to AE. 
Reporting of Serious Adverse Events A serious adverse event (SAE) is defined by federal regulation as 
any AE occurring at any dose that results in any of the following outcomes: death, life-threatening AE, 
hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, 
or a congenital anomaly/birth defect.  Serious adverse events occurring after signing the informed consent 
and during the follow-up period, including laboratory test abnormalities fulfilling the definition of SAE, 
whether or not considered related to the study medications or procedures, will be recorded on the Serious 
Adverse Event form and forwarded to the study PI as soon as possible.  The PI or designee will forward 
the reports to appropriate authorities (DSM, FDA, NHLBI, Pharmaceutical supplier) according to the 
institutional guidelines. All adverse events will also we reported to the IRB according to the institutional 
AE reporting guidelines.  Every attempt will be made to collect discharge summaries for each 
hospitalization to provide further details. 
 
Collect Unused Study Drug: Unused drug will be collected and Visits 4 and 5; upon completion of the 
study, unused study drug will be collected and destroyed. 
 
 
6.2.1 Screening Evaluation 
Adults 18 and older, with physician diagnosed mild to severe persistent asthma will be screened.  After 
reviewing and signing informed consent, subjects that fulfill inclusion and exclusion criteria will be 
invited to participate.  
   
Consenting Procedure 
Single informed consent describing screening and study procedures.   
The study PI (Emily DiMango, MD) or the research study coordinator (Amanda Kramer) will conduct the 
consent process. 
Emily DiMango is a professor of medicine and pulmonologist and director of the John Edsall-John Wood 
Asthma Center at Columbia University Medical Center.  Amanda Kramer, B.S. has over 3 years of 
experience as a clinical research coordinator and has experience consenting and studying pulmonary 


Study Product Guidelines and Considerations 
25 of 38 
Version 1.5 
 
 
22July 2019 
patients during clinical studies in the John Edsall-John Wood Asthma Center. 
Any changes in the consent form will only occur after approval from the institutional IRB and the 
NCCIH. 
Documentation of the consent process and consent forms will be retained in a research study binder. 
Screening 
Visit 1: Screening Visit  
Sequence of events: 
● Identify patients that are adults 18 and older with physician-diagnosed mild to severe persistent 
asthma 
● Sign informed consent 
● Fulfill inclusion and exclusion criteria 
● Review of medical history 
● Record Demographics 
● Recording of medication use 
● Physical exam including vital signs by study MD or NP 
● Urine pregnancy test for women of child bearing age 
● Scoring on ACT ≤ 19 
● Scoring on basic spirometry before and after bronchodilator  
Required to be eligible: 
● Patients that are adults 18 and older with physician-diagnosed mild to severe persistent asthma 
● Signing informed consent 
● Fulfill inclusion and exclusion criteria 
● Using inhaled corticosteroids with or without inhaled long acting beta agonists or anti-muscarinics. 
● Scoring on ACT ≤ 19 
● Negative urine pregnancy test for women of child bearing age 
 
Screening must be completed 14-21 days prior to visit 2 during which the ACT score will be confirmed to 
be ≤ 19, and the baseline FEV1 is ≥ 60% of predicted (or 1.5L); Baseline methacholine PD20 will be 
determined at V2 as a subsequent eligibility criterion. 
 
Visit 2; Day 14 to 21: 
 Administer ACT. If ACT remains ≤19, proceed .  If ACT > 19 consistent with good asthma 
control, terminate from study. 
 Confirm medication washouts (reschedule if not met). 
 Spirometry 
 methacholine bronchoprovocation testing if FEV1 is ≥ 60% or 1.5L (reschedule or terminate if < 
60% or 1.5L) to assess baseline methacholine PD20.  
 Administer BD for Methacholine Recovery Challenge 
 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
A single informed consent form will be used for screening and enrollment.  The enrollment date will be 
defined as the date that all of the screening criteria are met and the individual agrees to participate. 
The enrollment date will be recorded on the case report form and the allowable window from enrollment 
to randomization will be 15-22 days. 
Baseline Assessments 
● Baseline FEV1 
● Baseline methacholine PD20  
● Baseline ACT score 


Study Product Guidelines and Considerations 
26 of 38 
Version 1.5 
 
 
22July 2019 
● Baseline QOL and Asthma 2 week recall questionnaires 
● Baseline GI symptoms 
● Baseline Exhaled Nitric Oxide 
● Blood draw for eosinophils, cytokines, biomarkers 
● Blood draw for metabolite measurements in subjects participating in PK study 
 
Randomization 
Randomization to initiation of study intervention will occur on the same day.  Randomization will occur 
at visit 3 and will precede an intervention (i.e. starting of oral ginger or placebo). 
Randomization is a process that assigns participants/subjects by chance (rather than by choice) into 
specific groups, typically for clinical research and clinical trials. An independent statistican will generate 
the randomization codes and allocations. The blinded study coordinator will retrieve the randomization 
allocation through RedCap. RedCap is an institutionally available automated system for randomization 
and the independent statistician will have direct oversight over the process. The blinded study team will 
not have access to the randomization codes.  In this module, randomization model is defined as Drug A 
and Drug B in a 1:1 ratio. Drug A and Drug B may refer to placebo or active drug, however they are left 
coded as such to ensure blinding. The module creates a template allocation table, which the user uses to 
structure the randomization table to be imported. The module also monitors the overall allocation 
progress and assignment of randomized subjects to ensure balanced proportions of active drug and 
placebo.  Only one site member will be allowed randomization priviledges, but the site will confirm, and 
lock the specific data field to ensure that no data is altered after randomization. There is no stratification, 
and there are no variable block sizes..    
6.2.3 Blinding 
Ginger extract and placebo capsules have been pre-packaged and labeled with a code by the distributor 
(Atrium Innovations, Pure Encapsulations) and delivered to the research pharmacy at the Columbia 
University Medical Center. We do not anticipate any collected data offering evidence of a participant’s 
assignment to a particular arm.  All study data is collected objectively without an opportunity for the 
collected data to identify the study arm.  For example, changes in methacholine PD20 and exhaled nitric 
oxide (primary outcomes) will vary over the course of the study in both ginger and placebo treated 
subjects.  These variations will not be able to offer evidence of group membership and will only be 
informative after analysis in the aggregate.  
 
The study PIs, Emily DiMango, MD, Charles Emala, MD are authorized to break the blind if there is a 
concern for subject safety, a serious adverse event or safety concerns raised by the DSMB.  The PIs will 
contact the independent statistician who will be holding the codes. The PIs, Research Coordinator, study 
statistician(s), subjects and research pharmacy will be blinded.  The research pharmacy will be notified as 
to randomization to drug A or B but will be unaware of which is ginger versus placebo. 
 
6.2.4 Followup Visits 
Visit 3 Day 15-22 RANDOMIZATION VISIT 
Procedures Performed:  
 Administer questionnaires (ACT, QOL, A2WR) 
 Review medical history, conmeds, and AEs since the screening visit  
 Confirm medication washouts (reschedule if not met) 
 Vitals  
 Urine Pregnancy Test (if applicable) 
 Physical Exam  
 Review Randomization Inclusion/Exclusion Criteria 
 Baseline GI side effect check list 
 Randomize 
 Measure Exhale Nitric Oxide (FeNO) 


Study Product Guidelines and Considerations 
27 of 38 
Version 1.5 
 
 
22July 2019 
 Pre-dose Spirometry 
 Blood draw cytokines, biomarkers and blood eosinophil count 
 Pre-dose Pharmacokinetic blood draw for select subjects 
 Administer 1st dose of study drug 
 Post-Dose Spirometry (1 hr post-study drug dosing)  
 Pharmacokinetic blood draw for select subjects (n =8  4 Males & 4 Females) (Time 0.5, 1, 2, 3, 4 & 
8 hrs)- PK Subgroup only. 
 Dispense drug 
 
Visit 3A Day 29-36: Phone contact to answer questions and encourage compliance. 
 
Visit 4 Day 43-50 (Day 28 of study drug):  
Procedures Performed:  
 Administer questionnaires (ACT, QOL, A2WR) 
 Review conmeds, and AEs since V3  
 Review study drug compliance (pill count) 
 Confirm medication washouts (reschedule if not met) 
 GI side effect checklist 
 Vitals  
 Urine Pregnancy Test (if applicable) 
 Physical Exam  
 Exhale Nitric Oxide (FeNO) 
 Spirometry 
 Perform Methacholine Challenge --- reschedule visit if FEV1 is < 60% or 1.5L 
 Administer bronchodilator  
 Methacholine Recovery Challenge 
 Blood draw cytokines, biomarkers and blood eosinophil count 
 Pre-dose Pharmacokinetic blood draw--PK subgroup only. 
 Study Drug Dosing 
 Pharmacokinetic blood draw (Time 0.5, 1, 2, 3, 4 & 8 hrs)—PK subgroup only. 
 
Visit 4A Day 44-70: Phone or email contact to answer questions and encourage compliance. 
 
Visit 5 Day 71-78 (Day 56 of study drug) 
 Procedures Performed:  
 Administer questionnaires (ACT, QOL, A2WR) 
 Review conmeds, and AEs since the previous visit (V4) 
 Review study drug compliance (pill count) 
 Confirm medication washouts (reschedule if not met).  
 GI side effect check list 
 Vitals  
 Urine Pregnancy Test (if applicable) 
 Physical Exam  
 Exhale Nitric Oxide (FeNO) 
 Spirometry 
 Perform Methacholine Challenge --- reschedule visit if FEV1 is < 60% or 1.5 L 
 Administer bronchodilator  
 Methacholine Recovery Challenge 
 Collect Blood for cytokines, biomarkers and eosinophil count 
 Pre-dose Pharmacokinetic blood draw--PK subgroup only. 
 Study Drug Dosing for PK group only 
 Pharmacokinetic blood draw (Time 0.5, 1, 2, 3, 4 & 8 hrs)—PK subgroup only. 
 Collect unused study drug. 


Study Product Guidelines and Considerations 
28 of 38 
Version 1.5 
 
 
22July 2019 
 
6.2.5 Completion/Final Evaluation 
Visit 5 Day 71-78 (Day 56 of study drug) 
 Procedures Performed:  
 Administer questionnaires (ACT, QOL, A2WR) 
 Review conmeds, and AEs since the previous visit (V4) 
 Review study drug compliance (pill count) 
 Confirm medication washouts (reschedule if not met).  
 GI side effect check list 
 Vitals  
 Urine Pregnancy Test (if applicable) 
 Physical Exam  
 Exhale Nitric Oxide (FeNO) 
 Spirometry 
 Perform Methacholine Challenge --- reschedule visit if FEV1 is < 60% or 1.5 L 
 Administer bronchodilator  
 Methacholine Recovery Challenge 
 Collect Blood for cytokines, biomarkers and eosinophil count 
 Pre-dose Pharmacokinetic blood draw--PK subgroup only. 
 Study Drug Dosing 
 Pharmacokinetic blood draw (Time 0.5, 1, 2, 3, 4 & 8 hrs)—PK subgroup only. 
 Collect study drug. 
 
Any subjects who discontinue the study early will be contacted to determine the reason why.  These 
reasons will be documented in the study binder.  If termination occurs to lack of tolerance or adverse 
events related to the study drug or procedures, protocols for reporting adverse events will be followed as 
outlined below. 
7. SAFETY ASSESSMENTS  
Bronchodilator: (albuterol/salbuterol) will be available to be administered if the participant is 
uncomfortable from the effects of the methacholine challenge test, and also be used for reversibility testing 
after spirometry at V1. These drugs can lead to tremor, nervousness, tachycardia, palpitations and headache 
– these reactions are transient and rare (<5%) with the proposed doses used for this study, and if they occur, 
we will monitor the patient until they return to baseline.  High doses may cause arrhythmias and 
hypokalemia: these are very unlikely with the doses used for this study. 
 
Exhaled NO (FeNO): Exhaled breath will be collected from forced expirations using disposable 
mouthpieces for the online exhaled NO (Circassia) procedure described in the American Thoracic Society 
(ATS) guidelines. There are no known risks involved with breathing into the collection system. 
GI side effects: Patients will be asked about the frequency and severity of GI symptoms including 
eructation, heartburn, nausea, bloating or indigestion. 
Methacholine challenge: involves the inhalation of an agonist to induce bronchoconstriction and may 
induce the symptoms of an asthma exacerbation (chest tightness, dyspnea, coughing).  The procedure is 
performed in a closely monitored clinical environment, with availability of bronchodilator.  This procedure 
has been safely used in many previous studies by our group; we will only perform this procedure if the 
baseline FEV1 is > 60% predicted.  
 
Questionnaires and assessments: Participants will be asked to provide information about their 
psychological, physical, and medical functioning on questionnaires.   
  


Study Product Guidelines and Considerations 
29 of 38 
Version 1.5 
 
 
22July 2019 
Asthma Control Test (ACT). The self-administered validated ACT will be used for this measurement.  
 
Juniper mini-Asthma specific quality of life (mini AQOL). Disease specific quality of life will be 
measured via the Juniper mini-Asthma Quality of Life questionnaire, a validated questionnaire. 
 
2 week recall questionnaire: The Asthma two week recall (A2WR) was developed to capture the inherent 
intensity of the disease in individuals with asthma. It quantifies severity by combining information about 
impairment, risk, and the amount of medication required to maintain control.  
 
Pulmonary Function Testing: requires deep and forceful respiratory efforts. It is a commonly performed 
and safe examination that is widely performed in patients with lung disorders. Some patients report chest 
soreness the day following the procedure. Some patients may experience light-headedness during the forced 
expiration. The risk of syncope is mitigated by having the patient perform the test in the seated rather than 
standing position.  
 
Venous Blood Draw: For each blood draw, approximately 10 ml of venous blood will be drawn by 
phlebotomy from an upper extremity. For patients who consent to the pharmacokinetics study, an 
additional 105 ml of blood will be required. Blood drawing may cause a small amount of pain. In 
addition, a temporary bruise may develop. Rarely, people faint after blood drawing. Very rarely, the vein 
in which the needle has been inserted may become inflamed or infected.  
 
Ginger is widely used as an over-the-counter dietary supplement. The formulation and amount of 
ginger used in this study (2g per day; Pure Encapsulations®) has been chemically characterized by 
HPLC and has been administered to patients at the oral amount (2 grams) for 28 days in multiple human 
studies measuring inflammatory mediators in colonic mucosal biopsies. The incidence of side effects in a 
28 day trials of 30 individuals were not significantly different in placebo versus ginger and no adverse 
events were greater than the NCI Common Toxicity Criteria Grade 1. In a second study of 27 individuals 
no adverse event greater than NCI Common Toxicity Criteria Grade 1 was reported (no placebo 
comparison) and the leading complaints were gastrointestinal symptoms of eructation, heartburn or 
indigestion.7 In a third study of 20 patients consuming the same formulation in the same amount for the 
same duration (2g, Pure Formulations, 28 days) no statistically significant increase in adverse events 
occurred compared to placebo, no toxicities were greater than the NCI Common Toxicity Criteria Grade 1 
and included bloating, nausea and heartburn.16 
 
There have been small numbers of studies reporting on possible  inhibition of platelet aggregation by 
ginger. Ginger has been shown an in vitro study to inhibit platelet aggregation with a potency similar to 
that of aspirin and in another study of human volunteers, to have a syngergistic effect with nifedipine in 
platelet aggregation.8-10  A single case report has been published demonstrating epistaxis in a women who 
was being treated with Coumadin who subsequently started taking ginger.11 Subjects taking anti-
coagulation will be excluded from participation, though subjects taking aspirin alone will be included in 
the study since there have been no studies or reports of increased bleeding risk with aspirin and ginger 
combined.  
   
7.1 
Specification of Safety Parameters 
●Methacholine challenge involves the inhalation of an agonist to induce bronchoconstriction and may 
induce the symptoms of an asthma exacerbation (chest tightness, dyspnea, coughing).  The procedure is 
performed in a closely monitored clinical environment, with availability of bronchodilator.  This 
procedure has been safely used in many previous studies by our group; we will only perform this 
procedure if the baseline FEV1 is > 60% predicted.  
●Bronchodilator (albuterol/salbuterol) will be available to be administered if the participant is 
uncomfortable from the effects of the methacholine challenge test. 
●GI side effects will assessed at each study visit.  
●Venous Blood Draw: Rarely, people faint after blood drawing and therefore will be seated during blood 
draws. Very rarely, the vein in which the needle has been inserted may become inflamed or infected. 


Study Product Guidelines and Considerations 
30 of 38 
Version 1.5 
 
 
22July 2019 
 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
●Pulmonary function testing: (spirometry or methacholine provocation) adverse effects are immediately 
apparent during the test and will be treated (albuterol inhaler) and recorded in the case report forms. 
●GI side effects:7,16  This will be assessed at each study visit to ensure tolerance of the ginger capsules 
and will be recorded in the case report forms.  Evidence of GI intolerance will be addressed as detailed in 
adverse events below. 
●Venous Blood Draw: Rare fainting during blood draws occurs due to a vaso-vagal response and is 
immediately apparent.  Subjects will have their blood pressure and heart rate assessed and will be 
monitored until they return to normal. Very rarely, the vein in which the needle has been inserted may 
become inflamed or infected.  Blood draw sites will be inspected at each clinic visit. 
7.3 
Adverse Events and Serious Adverse Events  
An Adverse Event (AE) is any unfavorable and unintended symptom, or disease temporally associated 
with the administration of ginger or the clinical testing proposed that may or may not be considered 
related to the medical treatment or procedure. Adverse events will be recorded regardless of their 
relationship to the study intervention. 
Defining: A serious adverse event (SAE) is one that meets one or more of the following criteria: 
 Results in death 
 Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
 Results in inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect   
An important medical event that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
Adverse Event solicited and unsolicited: 
Solicited at each study visit: 
 
●Gastrointestinal side effects (including eructation, heartburn, nausea, bloating or indigestion) 
 
●Venipuncture complications (swelling, infection) 
Unsolicited at each study visit: 
●Patients will have a general medical examination and vital signs at every visit.  
 
7.4 
Reporting Procedures 
Reporting: SAEs that are unanticipated, serious, and possibly related to the study intervention will be 
reported to the Independent Monitors(s), IRB, FDA, and NCCIH in accordance with requirements.  To 
satisfy the requirement for prompt reporting, unanticipated problems will be reported using the following 
timeline:   
 
Unanticipated problems that are serious adverse events will be reported to the IRB within 48 
hours and to the Independent Safety Monitor(s) and to the NCCIH within 7 days of the 
investigator becoming aware of the event.  
 
Any other unanticipated problem will be reported to the IRB, Independent Safety Monitor(s), and 
NCCIH within 14 days of the investigator becoming aware of the problem.  
All unanticipated problems should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and OHRP within 
one month of the IRB’s receipt of the report of the problem from the investigator. 
Reporting to the FDA for the IND:  


Study Product Guidelines and Considerations 
31 of 38 
Version 1.5 
 
 
22July 2019 
 7-day IND Safety Report (unexpected fatal or life-threatening AEs related to the intervention); a 
copy of the report sent to the FDA will be submitted to the NCCIH Program Officer and 
Independent Safety Monitor(s) within 24 hours of FDA notification.  
 15-day IND Safety Report (any other serious and unexpected AE related to the intervention); a 
copy of the report submitted to the FDA will be submitted to the NCCIH Program Officer and 
Independent Safety Monitor(s) within 24 hours of FDA notification.  
 All other AEs documented during the course of the trial will be reported to NCCIH on an annual 
basis by way of inclusion in the annual report and in the annual AE summary which will be 
provided to NCCIH and to the Independent Monitors.  The Independent Safety Monitor(s) Report 
will state that all AEs have been reviewed. 
 
7.5 
Followup for Adverse Events 
Subjects will be followed up as outpatients for adverse events that are not serious adverse events.  
Subjects will be followed up until symptoms of adverse events resolve.  For serious adverse events, 
subjects will be followed up as an inpatient or outpatient as deemed appropriate by the treating physician.  
The follow up will continue until the adverse event is resolved or stabilized.  
7.6 
Safety Monitoring  
Dr. Jeanine D’Armiento, a pulmonologist, and Dr. Caleb Ing, a physician and epidemiologist, will serve 
as the data and safety monitors for the proposed study.  
 
8. INTERVENTION DISCONTINUATION  
Adverse gastrointestinal events associated with the consumption of ginger that require medical intervention 
(intravenous fluid administration, hospital admission) will  prompt temporary suspension of enrollment 
and/or study interventions until a complete safety review is convened.  Adverse reactions to inhaled 
methacholine that require hospital admission will  prompt temporary suspension of enrollment and/or study 
interventions until a complete safety review is convened.   Subsequent review of serious, unexpected, and 
related AEs by the DSMB, Independent Safety Monitor(s), IRB or the FDA may also result in suspension 
of further study interventions/administration of study product. The FDA retain the authority to suspend 
additional enrollment and study interventions/administration of study product for the entire study, as 
applicable. 
Participants will continue to be followed with their permission if study intervention is discontinued.  
Temporary discontinuation of treatment would interrupt the consecutive 56 day treatment plan and thus 
subjects would be removed from the study.  If a subject is removed from the study, evaluations related to 
any adverse events would be continued as defined in section 7.5 above. 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
We hypothesize that the oral consumption of Pure Encapsulation® ginger extract (2g/day by adult 
patients with moderate to severe asthma despite normal maintenance medications, will have an 
improvement in their tolerance to inhaled methacholine or a reduction in lung inflammation over the 56 
day treatment period.  
 
This is a randomized, double blind, placebo-controlled design.  Patients will have baseline measurements 
of their pulmonary function and inflammation status and will then be randomized to ginger extract or 
placebo.  The same measurements of pulmonary function and inflammation status will be repeated at 28 
and 56 days of ginger or placebo consumption.  The durations of 28 and 56 days were chosen because it is 
hypothesized that the primary benefit of consumption of oral ginger will be an anti-inflammatory effect in 


Study Product Guidelines and Considerations 
32 of 38 
Version 1.5 
 
 
22July 2019 
the lung that over time results in improved pulmonary function.   
Primary hypotheses: are that the oral daily consumption of ginger will improve the tolerance to inhaled 
methacholine and/or a reduction in exhaled nitric oxide.   
Secondary hypotheses: are that an additional measure of pulmonary function will improve (an increase in 
baseline FEV1) and/or that secondary measures of inflammation (eosinophilia, asthma associated 
cytokines) will improve. 
Primary outcome measures:  The primary outcome measures are methacholine (PD20) and exhaled nitric 
oxide. These outcomes will be measured at visit 3 (baseline) and visits 4 and 5 (days 28 and 56 of the oral 
ginger or placebo consumption). 
 
Secondary outcome measures: A clinically significant increase in baseline FEV1 of 100ml.  For subjects 
with eosinophilia (>300 cells/ul) a 32% decrease in blood eosinophils17, a 40% decrease in serum IL418,19, 
a 50% decrease in serum IL520 or a 75% decrease in serum IL13.21   
9.2 
Sample Size and Randomization 
We utilized published literature to identify the magnitude of change in our primary outcomes that are 
clinically relevant.  As illustrated in the table in section 3, we calculated a need of 14 subjects per arm for 
the methacholine measurement and 16 subjects per arm for the exhaled nitric oxide assessment (same 
subjects studied in methacholine and exhaled nitric oxide assays).  Thus we need 16 subjects per arm and 
anticipate a 10% attrition rate overall requiring 36 subjects.    As illustrated in the table in section 3, an 
enhanced tolerance to inhaled methacholine of 0.7X the doubling dose is considered clinically 
significant.12 We anticipate a S.D. of 0.6 in both groups and aim to achieve 80% power at the 0.05 
significance level.  This requires 14 subjects for each of the two arms.  For exhaled nitric oxide with 
baselines starting at >50ppb, a 20% decrease is considered clinically significant. We expect a S.D. of ~ 37 
and aim to achieve 80% power at the 0.05 level and will thus require 16 subjects for each of two arms.  
Treatment Assignment Procedures 
Subjects will be randomized to treatment A or B in a blinded fashion using the randomization algorithm 
within REDCap. The randomization module in REDCap implements a defined randomization model 
within the project, allowing the site to randomize the subjects. In this module, randomization model is 
defined as Drug A and Drug B in a 1:1 ratio. Drug A and Drug B may refer to placebo or active drug, 
however they are left coded as such to ensure blinding. The module creates a template allocation table, 
which the user uses to structure the randomization table to be imported. The module also monitors the 
overall allocation progress and assignment of randomized subjects to ensure balanced proportions of 
active drug and placebo.  Only one site member will be allowed randomization priviledges, but the site 
will confirm, and lock the specific data field to ensure that no data is altered after randomization. There is 
no stratification, and there are no variable block sizes. 
 
Trial randomization codes for each individual subject will be retained within the REDCap data set as 
treatment A or B.  The independent statistician retains the identity of A or B and does not disclose this to 
the study conductors.  The planned breaking of the code will occur after data analysis is complete.  
Unplanned breaking of the code will occur if a medical condition mandates such an action.  
 
Ginger extract and placebo capsules have been pre-packaged and labeled with a code by the distributor 
(Atrium Innovations, Pure Encapsulations) and delivered to the research pharmacy at the Columbia 
University Medical Center. We do not anticipate any collected data offering evidence of a participant’s 
assignment to a particular arm.  All study data is collected objectively without an opportunity for the 
collected data to identify the study arm.  For example, changes in methacholine PD20 and exhaled nitric 
oxide (primary outcomes) will vary over the course of the study in both ginger and placebo treated 
subjects.  These variations will not be able to offer evidence of group membership and will only be 
informative after analysis in the aggregate.  
 


Study Product Guidelines and Considerations 
33 of 38 
Version 1.5 
 
 
22July 2019 
The study PIs, Emily DiMango, MD, Charles Emala, MD are authorized to break the blind if there is a 
concern for subject safety, a serious adverse event or safety concerns raised by the DSMB.  The PIs will 
contact the research pharmacy who will be holding the codes. 
No stratification of the randomization will occur. 
9.3  
Definition of Populations 
Adults aged 18 years and above, with mild to severe persistent asthma will be enrolled.  Subjects will 
have asthma which is not optimally controlled despite the current use of inhaled corticosteroids with or 
without inhaled long-acting beta agonists. The populations will be those subjects randomized to the 
placebo arm versus ginger extract arm.  
All randomized subjects will be included in the primary analysis, analyzed based on intention-to-treat. In 
addition, a secondary analysis based on per protocol will be conducted. Per protocol analysis will exclude 
patients who missed 30% or more of their assigned treatment.  Please refer to section 5.4 for the equation 
to calculate compliance. 
9.4 
Interim Analyses and Stopping Rules 
No interim analysis is planned.  Due to the extensive use of this same formulation of ginger extract in the 
same daily dose, we expect no safety concerns and excellent tolerance. We have greatly exceeded these 
enrollment numbers in numerous previous asthma clinical studies in the John Edsall-John Wood Asthma 
Center at Columbia University Medical Center and believe that it is highly unlikely that this study will 
demonstrate poor study performance. 
Adverse gastrointestinal events associated with the consumption of ginger that require medical 
intervention (intravenous fluid administration, hospital admission) will  prompt temporary suspension of 
enrollment and/or study interventions until a complete safety review is convened.  Adverse reactions to 
inhaled methacholine that require hospital admission will  prompt temporary suspension of enrollment 
and/or study interventions until a complete safety review is convened.   Subsequent review of serious, 
unexpected, and related AEs by the DSMB, Independent Safety Monitor(s), IRB or the FDA may also 
result in suspension of further study interventions/administration of study product. The FDA retain the 
authority to suspend additional enrollment and study interventions/administration of study product for the 
entire study, as applicable. 
9.5 
Outcomes  
Outcomes will be analyzed when all patients have completed the study at day 56 by both PIs and the 
statistical consultant on this study (Shuang Wang, PhD) who will be blinded from the study group until 
the data analysis is completed. 
9.5.1 Primary Outcome   
The primary outcomes are a clinically significant change in tolerance to inhaled methacholine (PD20) or a 
clinically significant change in exhaled nitric oxide. These outcomes will be measured at visit 3 (baseline) 
and visits 4 and 5 (days 28 and 56 of the oral ginger or placebo consumption). 
9.5.2 Secondary Outcomes   
Secondary outcome measures: A clinically significant increase in baseline FEV1 of 100ml.  For subjects 
with eosinophilia (>300 cells/ul) a 32% decrease in blood eosinophils15, a 40% decrease in serum 
IL416,17, a 50% decrease in serum IL518 or a 75% decrease in serum IL13.19   
9.6 
Data Analyses  
We will compare the change in log-transformed methacholine reactivity (PD20) in the ginger versus the 
placebo group using two-sample t-test. We will compare patients’ initial PD20 (day 0) to their subsequent 
PD20 at days 28, 56 using paired t-test.  It is possible that the PD20 measurements on days 0, 28 and 56 
could be influenced by the consumption of oral ginger 1 hour prior so we will also compare the PD20 at 


Study Product Guidelines and Considerations 
34 of 38 
Version 1.5 
 
 
22July 2019 
day 0 to those at 28 and 56.  An acute benefit in methacholine tolerance will be reflected in a significant 
improvement between PD20’s at days 0, 28 and 56 while a chronic improvement will be reflected in 
improved PD20’s at days 28 and 56 compared to day 0. 
Patients with asthma have remarkably consistent fractional exhaled nitric oxide (FeNO) levels when 
measured over time with mild-moderate asthmatics having FeNO values of approximately 40 ± 10 ppb.22  
We will consider a 25% change in FeNO  as biologically significant23 comparing each patient’s initial 
FeNO to their subsequent FeNO at days 28, 56 using paired t-test. 
Data from prior studies does not support the existence of significant differences in the intervention effect 
between subgroups and thus subgroup analysis will not be performed. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Information for each participant will be collected by the lead study clinical coordinator (Amanda Kramer) 
and the PIs (Emily DiMango, MD and Charles Emala, MD) and recorded on case report forms (please see 
attachments under appendices, section 15 of this document) that will be electronically recorded within 
REDCap.  All 3 of these individuals will be blinded as to the study group of the subject.  
10.2 Data Management  
Access to clinical data will be limited to the clinical study coordinator, Dr. DiMango and Dr. Emala. All 
data will be stored within REDCap via desktop computers that are encrypted, password protected and 
physically located on the Columbia University campus. All participants will be assigned a unique non-
identifying number for which all their data and blood samples will be labeled. The key for this list will 
only be retained by the 3 individuals and devices named above. No personal identifying information will 
be available outside of this coded list on these protected devices. 
 
Data from this single site study will be stored within REDCap.  
The case report forms for each study visit are attached in the appendicies, section 15 of this document. 
10.3 Quality Assurance  
10.3.1 Training 
All individuals involved in this study have completed all institutional and IRB-required training for 
participation in human clinical trials including but not limited to GCP and HIPPA training.  The study 
coordinator has been trained in the administration of spirometry, methacholine provocation testing, 
administration of bronchodilators and phlebotomy.  All of these procedures will occur in a monitored 
clinical setting (the John Edsall-John Wood Asthma Center at Columbia University Medical Center). 
10.3.2 Quality Control Committee  
The PIs (Drs. DiMango and Emala) and study coordinator (Amanda Kramer) will meet monthly to review 
case report forms and study binders.   
10.3.3 Metrics 
Spirometry: Subjects will be asked to perform pulmonary function testing for collection of lung function 
data at each visit. Pulmonary function testing will be performed according to American Thoracic Society 
(ATS) guidelines (2005). Subjects will be tested using the same spirometry equipment at every visit. Up 
to 8 efforts will be performed to obtain 3 acceptable and reproducible test results. The best results from 
the 3 acceptable and reproducible efforts for PFTs will be recorded on the subject’s case report form and a 
copy of the spirometry reports will be retained with the subject’s source documents.  
Methacholine provocation: The spirometer will be calibrated daily as per ATS guidelines.  


Study Product Guidelines and Considerations 
35 of 38 
Version 1.5 
 
 
22July 2019 
10.3.4 Protocol Deviations 
Protocol deviations will be captured during subject visits.  This will occur by questioning of concurrent 
medications, appropriate washout of asthma-related medications, pill counts and 2 week recall 
questionnaires.  We will also include less than 70% study drug compliance as a protocol deviation.  These 
will be documented on case report forms.  Some deviations (e.g. failure to abide by washout criteria) will 
result in rescheduling of study visits until the washout period is achieved.  Deviations will be review 
monthly during scheduled meetings of Drs. DiMango, Emala and the research coordinator.  Significant 
deviations (e.g. failure to comply with consumption of ginger or placebo capsules, failure to appear for 
study visits within the allowed windows) will result in subject removal from the study. 
 
10.3.5 Monitoring 
 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol enrollment 
criteria) 
Monthly 
PIs & research study coordinator(s) 
Semi-annually 
Independent Monitors  
Caleb Ing, MD & Jeanine 
D’Armiento, MD, PhD 
Status of all enrolled subjects, as of 
date of reporting  
Monthly 
PIs & research study coordinator(s) 
Semi-annually 
Independent Monitors  
Caleb Ing, MD & Jeanine 
D’Armiento, MD, PhD 
Data entry quality control checks on 
5% of charts 
Quarterly 
Claire Goelst  (departmental 
clinical compliance coordinator) 
Adherence data regarding study visits 
and intervention 
Monthly 
PIs & research study coordinator(s) 
Adherence data regarding study visits 
and intervention 
AEs and rates (including out-of-range 
lab values) 
Semi-annually 
Independent Monitors  
Caleb Ing, MD & Jeanine 
D’Armiento, MD, PhD 
Monthly 
PIs & research study coordinator(s) 
AEs and rates (including out-of-range 
lab values) 
SAEs (unexpected and related) 
Semi-annually 
 
Independent Monitors  
Caleb Ing, MD & Jeanine 
D’Armiento, MD, PhD 
Annually 
NCCIH, FDA (If Applicable) 
Per occurrence 
PIs &  Independent Monitors  
Caleb Ing, MD & Jeanine 
D’Armiento, MD, PhD  
NIH/NCCIH, FDA (if applicable) 
SAEs (expected or unrelated) 
Per Occurrence 
PIs &Claire Goelst (departmental 
clinical compliance coordinator) 
SAEs (expected or unrelated) 
Unanticipated Problems 
Annually 
Independent Monitors  
Caleb Ing, MD & Jeanine 
D’Armiento, MD, PhD  
NIH/NCCIH 


Study Product Guidelines and Considerations 
36 of 38 
Version 1.5 
 
 
22July 2019 
  
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent document and any subsequent modifications will be reviewed and 
approved by the IRB for oversight of the study. The consent form is separate from the protocol document.  
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. Consent forms are available in the English 
and Spanish language. The consent form describes the purpose of the study, the procedures to be followed, 
and the risks and benefits of participation. A copy will be given to each participant and this fact will be 
documented in the participant’s record.  
11.3 Participant Confidentiality  
Participant data, which includes identifiable personal health information (PHI), will be collected at 
the clinical site. PHI will be stored in accordance with HIPAA regulations and local university and hospital 
policies. This includes the storage of PHI in locked cabinets or rooms, limited access to secure data areas 
by certified study personnel, password protection for electronic medical records, and explanation of HIPAA 
regulations on the study consent form. Analytic files will not contain personal identifiers (e.g. name, 
address). Reports/manuscripts will be prepared in such a way that individual participants cannot be 
identifiable.  
 
Data such as lung function or laboratory tests that are collected as part of this study may be 
transmitted to the participants treating physicians with the consent of the participant. Participants will be 
informed in the consent that PHI may also be disclosed for auditing purposes by the NIH or other regulatory 
bodies and is subject to subpoena.  
 
Personal identifiers (e.g. name, address, EMR number) are not transmitted to the Data and Safety 
Monitor or central laboratory in that all biospecimens and records are identified by a study ID, and other 
identifying information such as names are not entered into the central study database. Source records that 
are transmitted to the Data and Safety monitor for data quality audits have identifying information redacted. 
No highly confidential information is routinely collected, although the data collection does include PHI, so 
a breach of confidentiality would constitute a HIPAA violation.  
We will advise participants that the U.S. Department of Health and Human Services has the right to 
inspect medical records relating to this research for the purposes of verifying data. Where data are shared 
with other research entities, it will comply with the HIPAA definition of a limited dataset, and appropriate 
IRB approvals and waivers will be obtained. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCIH, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected.  
12. COMMITTEES 
The PIs (Emily DiMango,MD and Charles Emala,MD) will be responsible for the overall conduct of the 
study, data management, data analysis, publications and reports to respective committees (IRB, FDA, 
NCCIH, DSMB). 
A Data Safety Monitoring Board consisting of two individuals not affiliated with the study and without 
Monthly 
PIs & research study coordinator(s) 
Unanticipated Problems 
Per Occurrence 
IRB, FDA (if applicable) 


Study Product Guidelines and Considerations 
37 of 38 
Version 1.5 
 
 
22July 2019 
conflicts of interest with the PIs will meet with the PIs semi-annually or per occurrence for adverse events 
to review documents as detailed in the table above in section 10.3.5. 
13. PUBLICATION OF RESEARCH FINDINGS  
Any presentation, abstract, or manuscript will be made available for review by the NCCIH prior to 
submission.  
14. REFERENCES  
1. National Heart L, Blood Institute: National Asthma Education and Prevention Program; Expert Panel 
Reprot 3:Guidelines for the Diagnosis and Management of Asthma. 2007: 74 
2. Sondik EM, J.;Gentleman,J.: Summary Health Statistics for U.S. Adults: National Health Interview 
Survey 2011. Edited by Services USDoHaH. Vital and Health Statistics edition, Center for Disease 
Prevention and Control, 2012, pp 1-218 
3. Jobin MS, Moisan J, Bolduc Y, Dorval E, Boulet LP, Gregoire JP: Factors associated with the 
appropriate use of asthma drugs. Can Respir J 2011; 18: 97-104 
4. Singh BB, Khorsan R, Vinjamury SP, Der-Martirosian C, Kizhakkeveettil A, Anderson TM: Herbal 
treatments of asthma: a systematic review. J Asthma 2007; 44: 685-98 
5. Mali RG, Dhake AS: A review on herbal antiasthmatics. Orient Pharm Exp Med 2011; 11: 77-90 
6. Townsend EA, Siviski ME, Zhang Y, Xu C, Hoonjan B, Emala CW: Effects of ginger and its 
constituents on airway smooth muscle relaxation and calcium regulation. Am J Respir Cell Mol Biol 
2013; 48: 157-63 
7. Zick SM, Turgeon DK, Vareed SK, Ruffin MT, Litzinger AJ, Wright BD, Alrawi S, Normolle DP, 
Djuric Z, Brenner DE: Phase II study of the effects of ginger root extract on eicosanoids in colon 
mucosa in people at normal risk for colorectal cancer. Cancer Prev Res (Phila) 2011; 4: 1929-37 
8. Koo KL, Ammit AJ, Tran VH, Duke CC, Roufogalis BD: Gingerols and related analogues inhibit 
arachidonic acid-induced human platelet serotonin release and aggregation. Thromb Res 2001; 103: 
387-97 
9. Nurtjahja-Tjendraputra E, Ammit AJ, Roufogalis BD, Tran VH, Duke CC: Effective anti-platelet and 
COX-1 enzyme inhibitors from pungent constituents of ginger. Thromb Res 2003; 111: 259-65 
10. Young HY, Liao JC, Chang YS, Luo YL, Lu MC, Peng WH: Synergistic effect of ginger and 
nifedipine on human platelet aggregation: a study in hypertensive patients and normal volunteers. Am 
J Chin Med 2006; 34: 545-51 
11. Kruth P, Brosi E, Fux R, Morike K, Gleiter CH: Ginger-associated overanticoagulation by 
phenprocoumon. Ann Pharmacother 2004; 38: 257-60 
12. Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, 
DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, 
Israel E: KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 2017; 
376: 1911-1920 
13. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, 
Taylor DR, American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels 
for Clinical A: An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels 
(FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184: 602-15 
14. Pasha MA, Smith TC, Feustel PJ, Jourd'heuil D: Effects of low-dose fluticasone propionate/salmeterol 
combination therapy on exhaled nitric oxide and nitrite/nitrate in breath condensates from patients 
with mild persistent asthma. J Asthma 2013; 50: 64-70 
15. Zick SM, Ruffin MT, Lee J, Normolle DP, Siden R, Alrawi S, Brenner DE: Phase II trial of 
encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care 
Cancer 2009; 17: 563-72 
16. Zick SM, Turgeon DK, Ren J, Ruffin MT, Wright BD, Sen A, Djuric Z, Brenner DE: Pilot clinical 
study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased 
risk for colorectal cancer. Mol Carcinog 2014 
17. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, 
Chung KF, Djukanovic R, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ: Effects of an interleukin-5 


Study Product Guidelines and Considerations 
38 of 38 
Version 1.5 
 
 
22July 2019 
blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic 
response. Lancet 2000; 356: 2144-8 
18. Lama M, Chatterjee M, Nayak CR, Chaudhuri TK: Increased interleukin-4 and decreased interferon-
gamma levels in serum of children with asthma. Cytokine 2011; 55: 335-8 
19. Cui AH, Zhao J, Liu SX, Hao YS: Associations of IL-4, IL-6, and IL-12 levels in peripheral blood 
with lung function, cellular immune function, and quality of life in children with moderate-to-severe 
asthma. Medicine (Baltimore) 2017; 96: e6265 
20. Kato M, Yamada Y, Maruyama K, Hayashi Y: Differential effects of corticosteroids on serum 
eosinophil cationic protein and cytokine production in rhinovirus- and respiratory syncytial virus-
induced acute exacerbation of childhood asthma. Int Arch Allergy Immunol 2011; 155 Suppl 1: 77-84 
21. Janeva EJ, Goseva Z, Gjorchev A, Debreslioska A, Spiroski M, Zafirova B, Dimitrova MG: The 
Effect of Combined Therapy ICS/LABA and ICS/LABA plus Montelukast in Patients with 
Uncontrolled Severe Persistent Asthma Based on the Serum IL-13 and FEV1. Open Access Maced J 
Med Sci 2015; 3: 268-72 
22. Kharitonov SA, Gonio F, Kelly C, Meah S, Barnes PJ: Reproducibility of exhaled nitric oxide 
measurements in healthy and asthmatic adults and children. Eur. Respir J 2003; 21: 433-438 
23. Syk J, Malinovschi A, Johansson G, Unden AL, Andreasson A, Lekander M, Alving K: Anti-
inflammatory treatment of atopic asthma guided by exhaled nitric oxide: a randomized, controlled 
trial. J Allergy Clin. Immunol. Pract 2013; 1: 639-648 
 
15. SUPPLEMENTS/APPENDICES 
Consent Form 
Case Report Forms 

ICF_000.pdf: 
 
 
Attached to Protocol: IRB-AAAR8427
Principal Investigator: Emily Dimango (ead3)
IRB Protocol Title: Ginger’s therapeutic potential in asthma
 
 
 
Consent Number: CF-AACA1150
Participation Duration: 78 days
Anticipated Number of Subjects: 36
Research Purpose: The purpose of this study is to test the effect of oral ginger on airway hyper responsiveness and
inflammatory cell mediators in adult patients with Asthma.
 
 
 
 
WHAT INFORMATION IS IN THIS FORM?
The purpose of this form is to give you information to help you decide if you want to take part in a research study. This
consent form includes information about:
 
- why the study is being done;
- the things that you will be asked to do if you are in the study;
- any known risks involved;
- any potential benefit;
- options, other than taking part in this study, that you have.
Columbia University Consent Form
Protocol Information
General Information
Contacts
Contact
Title
Contact Information
Emily Dimango
Principal Investigator
Phone:
212-305-0631
Email:
ead3@columbia.edu
Tarnjot Saroya
Coordinator
Phone:
212-305-0251
Email:
tks2127@cumc.columbia.
edu
Information on Research
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 1 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


 
The principal investigator (the lead researcher for this project) will discuss the study with you. If at any time you have
questions about the study, please ask a member of the study team. Take all the time you need to decide whether you
want to take part in this research study.
 
We are asking you to take part in a research study.
 
This form explains why we are doing this study and what you will be asked to do if you choose to be in this study. It
also describes the way we (Researchers) would like to use and share information about you. Please take the time to
read this form.  We will talk to you about taking part in this research study. You should ask us any questions you have
about this form and about this research study.
You do not have to participate if you don't want to.
 
WHY IS THIS STUDY BEING DONE?
 
We are doing this research study to find out if an herbal supplement, ginger, can help people who have asthma. We
are trying to understand if ginger reduces inflammation in the airways of people with asthma.
 
WHAT WILL I BE ASKED TO DO IF I CHOOSE TO BE IN THIS STUDY?
 
We will ask you to come to the Asthma Center in Presbyterian Hospital. 
 
We will ask you to complete 3 surveys.
 
If subjects qualify for the study, you will be randomized to take either ginger capsules twice per day or placebo
capsules twice per day for 56 days.
 
We will ask you to give a blood sample of two teaspoons of blood 3 times over the nearly 3 months of the study.  Blood
will be drawn by the study physician or the study coordinator at the study center from a vein in your arm, after the area
is cleaned with an alcohol swab. The blood will be drawn by the study staff  and sent to the clinical laboratory at
Columbia or to a research laboratory.
 
If you consent to participate in the PK sub-study, you will be asked to withhold your study drug at Visits 4 and 5.
 
If you test positive for COVID-19 at any point of the study, you will be terminated early.
 
Note: All methacholine bronchoprovocation procedures (on visits 2, 4, and 5) have been removed from the study visits
due to the Covid-19 pandemic.
 
The following tests and procedures will be done on scheduled visits:
 
Covid-19 Nasal swab test 1: 1-3 days before Visit 1.
 
Day 0/Visit 1: Screening Visit: review of medical history, recording of medication use, physical exam by study MD or
NP and pulmonary function test (spirometry) before and 15 minutes after inhaling four puffs of a short acting
bronchodilator. You will then be asked to continue your usual asthma medications for the 14-21 day screening period.
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 2 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


You will be asked to complete a questionnaire.
 
Day 14-21/Visit 2: You will be asked to complete one questionnaire. You will be asked to withhold some of your
inhalers for a pre-specificed time (withhold albuterol for at least 6 hours and withhold long acting bronchodilator for at
least 24 hours). Women of child bearing potential will have a urine pregnancy test checked. You will undergo
spirometry, and then a methacholine bronchoprovocation testing which involves inhaling increasing concentrations of
nebulized methacholine and closely monitoring your lung function to determine the dose that causes a 20% drop in
lung function.
Note: Study Visit 2 has been eliminated due to Covid-19 pandemic.
 
Covid-19 Nasal swab test 2: 1-3 days before visit 3.
 
Day 15-24/Visit 3 Randomization Visit:
1-3 days after the methacholine testing, you will be randomized (similar to flipping a coin) into one of two treatment
groups; oral ginger (1 g twice per day: Pure Encapsulations™) or matching placebo. You will be asked to take 2
capsules, each containing 500 mg of ginger, or placebo each morning and evening for 56 days.
At this visit, pulmonary function (spirometry) will be measured, women of child bearing potential will have a pregnancy
test confirmed, you will be asked to complete three questionnaires about your asthma symptoms. We will measure
inflammation in your lungs by asking you to breath into a machine that measures a gas called nitric oxide. 10 ml (two
teaspoons) of blood will be collected from a vein in your arm for measurement of mediators which serve as markers for
inflammation in your lungs. You will then be given your first dose of study drug and the breathing test (spirometry) will
be repeated one hour later. PK samples will be collected to measure ginger compounds in the blood, with another 35
ml of blood from select subjects.
 
Covid-19 Nasal swab test 3: 1-3 days before visit 4. 
 
Day 43-50/Visit 4: At this visit, pulmonary function (spirometry) will be measured, women of child bearing potential will
have a pregnancy test confirmed, you will be asked to complete three questionnaires about your asthma symptoms.
We will measure inflammation in your lungs by asking you to breath into a machine that measures a gas called nitric
oxide. 10 ml (two teaspoons) of blood will be collected for measurement of inflammation in your lungs. A breathing test
(methacholine challenge) will be performed. You will then be given a dose of study drug. PK samples will be collected
to measure ginger compounds in the blood, with another 35 mL of blood from select subjects.
 
Covid-19 Nasal swab test 4: 1-3 days before visit 5. 
 
Day 71-78/Visit 5:
At this visit, pulmonary function (spirometry) will be measured, women of child bearing potential will have a pregnancy
test confirmed, you will be asked to complete three questionnaires about your asthma symptoms. We will measure
inflammation in your lungs by asking you to breath into a machine that measures a gas called nitric oxide. 10 ml (two
teaspoons) of blood will be collected to test for mediators that serve are markers of inflammation in your lungs. You will
then be given a dose of study drug. PK samples will be collected to measure ginger compounds in the blood, with
another 35 ml of blood from select subjects.
 
If you agree to a separate part of the study, we will collected an additional 35 ml (7 teaspoons) of blood from a vein in
your arm over 8 hours, at 6 additional time points, to measure the level of medication in your blood. This will occur at
visits 3, 4 and 5, for a total of 105 ml.
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 3 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


 
 
 
____ I agree to participate in this separate study
 
____ I do not agree to participate in this separate study
 
___________________________________________________________________________Print name and date
 
 
 
 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
General risks
 
There may be risks or discomforts if you take part in this study. These include:
 
COVID-19 Testing: A diagnostic test is performed by inserting a swab into your nose and twirling it around for a few
seconds. The swab sample will then be sent to the lab for results. Some subjects may experience a lachrymal reflex,
which may cause teary eyes as well as some minor discomfort.
 
Pulmonary Function Testing: This test requires deep and forceful respiratory efforts. It is a commonly performed and
safe examination that is widely performed in patients with lung disorders. Some patients report chest soreness the day
following the procedure. Some patients may experience light-headedness during the forced expiration. The risk of
syncope is mitigated by having the patient perform the test in the seated rather than standing position.
 
Methacholine challenge involves the inhalation of an agonist to induce bronchoconstriction and may induce the
symptoms of an asthma exacerbation (chest tightness, dyspnea, coughing). The procedure is performed in a closely
monitored clinical environment, with availability of bronchodilator. This procedure has been safely used in many
previous studies in our division and nationwide, we will only perform this procedure if your baseline lung function is
greater than a certain cutoff of 60%.
Note: Methacholine challenge tests have been removed from study visits 2,4, and 5 due to the Covid-19 pandemic.
 
Bronchodilator (albuterol/salbuterol) will be available to be administered if you are uncomfortable from the effects of
the methacholine challenge test. These drugs can lead to tremor, nervousness, tachycardia, palpitations and
headache – these reactions are transient and rare (<5%) with the proposed doses used for this study, and if they
occur, we will monitor you until you feel better.  High doses may cause arrhythmias and low potassium: these are very
unlikely with the doses used for this study.
 
Questionnaires and assessments: You will be asked to provide information about your psychological, physical, and
medical functioning on questionnaires.  The mini asthma quality of life questionnaire consists of 15 questions for which
Risks
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 4 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


you will be asked to check a scale of 1 to 7. This questionnaire takes approximately 10 minutes to complete. The
Asthma Control Test ("ACT") consists of 5 questions and takes less than 5 minutes to complete. The Asthma two
week recall (A2WR) has four questions regarding your asthma symptoms in the past two weeks and should take you
less than 5 minutes to complete.
 
Side effects of medication: Some previous studies of ginger have reported mild gastrointestinal side effects such as
bloating. If you experience these side effects, please let your study team know.
 
Drug interactions: It is possible that ginger can intensify the effect of anti coagulation drugs (eg blood thinners). Only
subjects not taking anticoagulants will be enrolled in the study. If for some reason, your doctor prescribes anti-
coagulation therapy, you will be withdrawn from the study.
 
While we will make every effort to protect privacy and keep data confidential, there is a risk that information can be
disseminated in ways that can risk the privacy of a person. To minimize risk, we will use only study codes to identify
data and study records, store study data and records in a secure place, and personal information such as names,
addresses, and telephone numbers will not be in the central database.
 
Venous Blood Draw: For each blood draw, approximately 10 ml (2 teaspoons) of venous blood will be drawn  from
your arm. Blood drawing may cause a small amount of pain. In addition, a temporary bruise may develop. Rarely,
people faint after blood drawing. Very rarely, the vein in which the needle has been inserted may become inflamed or
infected. Samples will be identified only by alphanumeric identifiers.
 
Exhaled NO (FeNO): Exhaled breath will be collected from forced expirations using disposable mouthpieces so that
we may measure inflammation in your lungs.  There are no known risks involved with breathing into the collection
system.
 
There may be other risks of taking part in this research study that we don't know about. If we learn about other risks,
we will let you know what they are so that you can decide whether or not you want to continue to be in the study.
 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
Potential direct benefit
 
You may or may not receive personal (direct) benefit from taking part in this study. The possible benefits of taking part
in this study include a possible improvement in asthma symptoms if the study medication is in fact helpful for asthma.
 
There may be no direct benefit for taking part in this research study,
 
You may not receive personal (direct) benefit from taking part in this research study, however the information collected
from this research may help others in the future.
 
 
Benefits
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 5 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


 
WHAT OTHER OPTIONS ARE THERE? 
You may choose not to take part in this research study.
 
You do not have to take part in this study to get treatment for your condition. The alternative to participating in this
study is not participating in the study.
 
 
 
WHAT ABOUT CONFIDENTIALITY? 
Any information collected during this study that can identify you by name will be kept confidential. We will do
everything we can to keep your data secure, however, complete confidentiality cannot be promised. Despite all of our
efforts, unanticipated problems, such as a stolen computer may occur, although it is highly unlikely.
 
Your data, biological samples, questionnaire responses and health information will be assigned a code number, and
separated from your name or any other information that could identify you. The research file that links your name to
the code number will be kept on a password-protected computer and only the investigator and study staff will have
access to the file.
 
The following individuals and/or agencies will be able to look at and copy your research records
- The investigator,  Columbia University staff, New York Presbyterian Hospital staff and other medical professionals
who may be evaluating the study
-Columbia University Medical Center has recently implemented a new electronic medical record (EMR) system, which
will be shared with Weill Cornell Medical Center and New-York Presbyterian Hospital and its affiliated institutions. Your
participation in this research study will be documented in our new EMR system. Medical records in this system can be
viewed by authorized personnel from these institutions. Study monitors and others who provide oversight of the study
may also need to access this record.
- Authorities from Columbia University including the Institutional Review Board ('IRB'), and other regulatory agencies
- The Office of Human Research Protections ('OHRP') and the United States Food and Drug Administration ('FDA');
-  the sponsor of this study, [the National Institutes of Health], including persons or organizations working with or
owned by the sponsor
 
 
 
 
WHAT IF I GET HURT WHILE I AM ON THE STUDY? 
 
Taking part in this research study may result in injury or harm to you. In the event of an injury resulting from your
participation in this study, you should seek appropriate medical care and inform the study doctor.  In the event of an
Alternative Procedures
Confidentiality
Research Related Injuries
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 6 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


emergency you should go to an emergency room.
 
If you are injured or harmed as a result of participating in the study and receive medical care through the NewYork-
Presbyterian Hospital (NYPH), a Columbia doctor, or any other health provider, you will be sent a bill for whatever
medical care you receive. All or part of your bill may be paid by your health insurance.
 
Columbia University and NewYork-Presbyterian Hospital (NYPH) are not offering to provide you the drug after the
termination of the study or to pay you for pain, worry, lost income, the cost of your medical care or non-medical care
costs that might occur as a result of your taking part in this study. However, you do not waive any of your legal rights in
signing this form.
 
 
 
 
 
WILL I GET COMPENSATED? 
You will be compensated for your participation in the study as outlined below. There are 5 study visits (note: study visit
2 has been eliminated) and 4 COVID-19 testing visits. If you complete all study visits (visit 2 excluded), including
COVID-19 testing, you will get a total of $300. If you are part of the PK study, you will get a total of $595. If you miss
any of the visits, you will not be compensated for those visits. If you terminate the study early, you will receive an
amount based on the visits that you have completed.  Payment for each visit will be in the form of a pre-loaded credit
card that will be given to you. Reimbursement will be processed after completion of both covid-19 nasal swab and
subsequent study visit. If a subject has only completed a COVID-19 testing visit and cannot complete the subsequent
visit, he/she will be compensated $25.
 
Covid-19 Nasal Swab 1: $25
Visit 1: $50
Visit 2: $50 (Eliminated)
Covid-19 Nasal Swab 2: $25
Visit 3: $50
Covid-19 Nasal Swab 3: $25
Visit 4: $50
Covid-19 Nasal Swab 4: $25
Visit 5: $50
 
 
 
 
 
 
WHAT ARE THE COSTS? 
Compensation
Additional Costs
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 7 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


No cost
 
There are no costs to you for taking part in this study.
 
Taking part in this study will not involve additional costs to you. All study drugs will be given free of charge by the
sponsor. You and/or your insurance company will have to pay for any costs that are part of your regular medical care.
 
You will remain responsible for all insurance premiums, deductibles, copayments, and coinsurance amounts.
 
 
 
 
 
DO I HAVE TO BE IN THE STUDY? 
Voluntary Participation
 
Participation in this study is voluntary. Refusal to participate will involve no penalty or loss of benefits to which you are
otherwise entitled. You may discontinue participation at any time without penalty or loss of benefits to which you are
otherwise entitled.
 
This consent also confirms your permission for the study team to contact you by email or phone during the study to
encourage your compliance. Please verify with the research team which method of contact would be best for you.
 
 
 
 
 
WHAT CAN I EAT WITH THE STUDY DRUG?
We will be asking you to withhold eating foods that have high polyphenols, due to its interaction with Ginger. This will
include coffee, tea, fruits, vegetables, juice and supplement intakes of food. A full list of foods and drinks to avoid will
be provided to you by the research coordinator. We will only ask you to withhold this food up to three days before your
visits 4 and 5
 
Food will be provided for those who are dosing with study drug in clinic.
 
 
 
Statement of Consent
Voluntary Participation
Additional Information
Statement of Consent
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 8 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021


 
Statement of Consent
I have read the consent form and talked about this research study, including the purpose, procedures, risks, benefits
and alternatives with the researcher. Any questions I had were answered to my satisfaction. I am aware that by signing
below, I am agreeing to take part in this research study and that I can stop being in the study at any time. I am not
waiving (giving up) any of my legal rights by signing this consent form. I will be given a copy of this consent form to
keep for my records.
 
 
 
 
Participant Signature Lines
 
Study Subject
Print Name ____________________________  Signature _____________________________________________
Date & Time ___________________________
 
 
Research Signature Lines
 
Person Obtaining Consent
Print Name ____________________________  Signature _____________________________________________
Date & Time ___________________________
Signatures
Medical Center IRB: 212-305-5883
CF#: AACA1150  Copied From #: AABV4850
IRB-AAAR8427 (Y03M01)                                    Page 9 of 9
Printed on: 04/22/2021 at 19:36
IRB Approval Date: 08/20/2020
For use until: 06/23/2021