Phase IV Study Evaluating The Safety And Clinical Efficacy Of Elderberry Extract In Patients With Influenza: A Randomized, Double-Blind Placebo-Controlled Trial
Phase: PHASE4
Conditions: Influenza, Human
Sponsor: michael macknin

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
Page 1 of 31 
 
 
 
PEDIATRIC INSTITUTE 
CLEVELAND CLINIC  
 
 
 
 
PHASE IV STUDY EVALUATING THE SAFETY AND CLINICAL EFFICACY OF 
ELDERBERRY EXTRACT IN PATIENTS WITH INFLUENZA:  A RANDOMIZED, DOUBLE-
BLIND PLACEBO-CONTROLLED TRIAL 
NCT#03410862 
 
 
Sponsor/Principal Investigator:Michael Macknin, M.D. 
Professor of Pediatrics Cleveland Clinic Lerner College of Medicine of Case Western Reserve University 
9500 Euclid Avenue, Mail Code R3 
Cleveland, Ohio 44195 
macknim@ccf.org 216-444-5512 Office or 216-410-9418 Cell 
 
 
Co-Investigators:  
 
Co-Investigator: 
Dr. Sharon Mace M.D.  
Mail Code: 
E19 
Phone: 216-445-4598 
   
  
Mailing Address of all co-investigators: 9500 Euclid Avenue  Cleveland, Ohio  44195 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
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INVESTIGATOR’S SIGNATURE PAGE  
 
 
Protocol Number or Version: 
5.0 
 
Protocol Date: 
 
 
 8 November 2018 
 
 
PHASE IV STUDY EVALUATING THE SAFETY AND CLINICAL EFFICACY ELDERBERRY 
EXTRACT IN PATIENTS WITH INFLUENZA:  A RANDOMIZED, DOUBLE-BLIND 
PLACEBO CONTROLLED TRIAL 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable US federal regulations and ICH guidelines. 
 
Investigator: Michael Macknin, M.D. 
 
Signed: 
 
Date: 
 
 
 
 
 
 
 
 
Name and Address of Institution:  Cleveland Clinic 9500 Euclid Avenue 
 
 
 
 
            Cleveland, Ohio  44195 
 
 
 
 
            
 
 
 
 

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
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ABBREVIATIONS 
[Abbreviations or acronyms frequently used in the protocol] 
 
 
 
Example Abbreviations 
FDA 
Food and Drug Administration 
CRF 
Case Report Form 
IRB 
Institutional Review Board 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
DAIDS 
Division of AIDS Adverse Event Grading Table 
PHI 
Protected Health Information 
 
 
 
 

 
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Table of Contents 
TITLE ........................................................................................................................................................................... 1 
INVESTIGATOR’S SIGNATURE ............................................................................................................................ 2 
ABBREVIATIONS ...................................................................................................................................................... 3 
RESEARCH SCHEMA .............................................................................................................................................. 7 
1 
INTRODUCTION .............................................................................................................................................. 8 
1.1 
Background ................................................................................................................................... 8 
1.2 
Investigational Agent [if applicable] Information provided by manufacturer describing 
investigational drug. ................................................................................................................................. 8 
1.3 
Preclinical data .............................................................................................................................. 8 
1.4 
Clinical Data to Date ...................................................................................................................... 9 
1.5 
Dose Rationale and Risk/Benefits ................................................................................................. 9 
2 
STUDY OBJECTIVES ....................................................................................................................................... 9 
3 
STUDY DESIGN ............................................................................................................................................... 10 
3.1 
General Design ............................................................................................................................ 10 
3.2 
Study Endpoints .......................................................................................................................... 10 
3.3 
Primary Safety Endpoints ............................................................................................................ 10 
4 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................................... 10 
4.1 
Inclusion Criteria ......................................................................................................................... 10 
4.2 
Exclusion Criteria ......................................................................................................................... 11 
4.3 
Subject Recruitment and Screening ............................................................................................ 11 
4.4 
Early Withdrawal of Subjects ...................................................................................................... 11 
4.4.1 
When and How to Withdraw Subjects ................................................................................ 11 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .................................................... 12 
5 
STUDY SUPPLEMENT ................................................................................................................................... 12 
5.1 
Description .................................................................................................................................. 12 
5.2 
Supplement Regimen .................................................................................................................. 12 
5.3 
Method for Assigning Subjects to Supplement Groups .............................................................. 12 
5.4 
Preparation and Administration of Study Medication ................................................................ 12 
5.5 
Subject Compliance Monitoring ................................................................................................. 12 
5.6 
Prior and Concomitant Therapy .................................................................................................. 12 
5.7 
Packaging .................................................................................................................................... 13 
5.8 
Blinding of Study Medication ...................................................................................................... 13 
5.9 
Receiving, Storage, Dispensing and Return ................................................................................ 13 

 
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5.9.1 
Receipt of Study Medication ............................................................................................... 13 
5.9.2 
Storage ................................................................................................................................ 13 
5.9.3 
Dispensing, Return, and Destruction of Study Medications ............................................... 13 
6 
STUDY PROCEDURES .................................................................................................................................. 14 
6.1 
Pre-registration and Screening ................................................................................................... 14 
6.2 
Visit 1 ........................................................................................................................................... 14 
6.3 
Visit 2, etc. ................................................................................................................................... 14 
7 
STATISTICAL PLAN ...................................................................................................................................... 15 
7.1 
Sample Size Determination ......................................................................................................... 15 
7.2 
Statistical Methods ..................................................................................................................... 15 
7.3 
Subject Population(s) for Analysis .............................................................................................. 16 
8 
SAFETY AND ADVERSE EVENTS .............................................................................................................. 16 
8.1 
Definitions As Defined by Cleveland Clinic IRB-60 Adverse Event Reporting ............................. 16 
8.2 
Recording of Adverse Events ...................................................................................................... 17 
8.3 
Reporting of Serious Adverse Events .......................................................................................... 17 
8.3.1 
IRB Notification by Investigator ......................................................................................... 17 
8.3.2 
FDA Notification by Sponsor (if applicable) ...................................................................... 18 
8.4 
Unblinding Procedures ................................................................................................................ 18 
8.5 
Stopping Rules............................................................................................................................. 18 
8.6 
Medical Monitoring .................................................................................................................... 18 
8.7 
Criteria for Withdrawal of Patient from Study. .......................................................................... 18 
9 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 19 
9.1 
Confidentiality and Privacy ......................................................................................................... 19 
9.2 
Source Documents ...................................................................................................................... 19 
9.3 
Case Report Forms ...................................................................................................................... 19 
9.4 
Records Retention ....................................................................................................................... 19 
10 
STUDY MONITORING, AUDITING AND INSPECTING ......................................................................... 19 
10.1 
Study Monitoring Plan ................................................................................................................ 19 
10.2 
Auditing and Inspecting .............................................................................................................. 20 
11 
ETHICAL CONSIDERATIONS ..................................................................................................................... 20 
12 
PUBLICATION PLAN .................................................................................................................................... 20 
13 
REFERENCES .................................................................................................................................................. 20 
14 
ATTACHMENTS ............................................................................................................................................. 21 
14.1 
Screening/Enrollment Questionnaire ......................................................................................... 21 

 
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14.2 
Daily (Symptom) Questionnaire .................................................................................................. 25 
14.3 
Poster/Handout .......................................................................................................................... 27 
14.4 
Patient Take Home Checklist ...................................................................................................... 30 
 
 
 

 
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RESEARCH SCHEMA 
 
PHASE IV CLINICAL ACTIVITY/SAFETY 
1. Patients will be screened, and influenza polymerase chain reaction positive patients ages 5 
and above in the first 48 hours of symptoms will be enrolled at the time of presentation to 
Emergency Rooms at Main Campus, Fairview and Hillcrest Hospitals of Cleveland Clinic 
Health Care System.   
2. Patients will be randomized in a double-blind placebo-controlled trial to treatment with 
Elderberry Extract (SambucolR) or Placebo 15 ml. 4 times a day for 5 days ages 13 and 
above, and 15 ml 2 times a day for 5 days for ages 5-12.  All patients will also be offered a 
prescription for standard of care oseltamivir or baloxavir marboxil (Xofluza) treatment. 
3. Daily telephone questionnaires documenting compliance, symptoms, and side effects will be 
obtained until patients are completely recovered from influenza for 24 hours or reach 21 
days from date of enrollment.  All daily information will be recorded on a case report form, 
and then entered into REDCap Cloud. 
 
 
 
 

 
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1 INTRODUCTION 
1.1 Background 
We propose to conduct a randomized, double-blind, placebo-controlled trial of elderberry extract in a 
group of 65-100 patients with documented influenza who have been prescribed or offered a prescription 
for oseltamivir or baloxavir marboxil (Xofluza) . 
A recent evidence-based systematic review by the Natural Standard Research Collaboration concluded 
that there is good scientific evidence that elderberry extract supplementation provides effective relief for 
the symptoms of influenza.(1-4)  The fact all previously published elderberry extract supplementation 
studies have been small, did not have intent-to-treat analysis, and were not published in high impact 
journals  probably helps explain why their findings have not been generally recognized by the medical 
community and lay-public. 
The “CDC estimates that influenza in the United States has resulted in between 9.2 million and 60.8 
million illnesses, between 140,000 and 710,000 hospitalizations and between 12,000 and 56,000 deaths 
annually since 2010. (5)   If elderberry extract supplementation is shown to be associated with 
improvement of symptoms of influenza there could be a beneficial impact on health in the United States 
and the world.  
1.2 Investigational Agent [if applicable] Information provided by manufacturer 
describing investigational drug. 
See attachments below: 
Part 1.pdf
 
Part 2.pdf
 
Part 3.pdf
 
Part 4.pdf
 
1.3 Preclinical data 
A recent review of elderberry describes its potential mechanisms of action.  Elderberry has been reported 
“to modulate the inflammatory cytokines IL-1 and TNF-alpha in vitro, increase human basophil secretion 
of IL-4, IL-13, and histamine, inhibit macrophage release of proinflammatory cytokines, and contain 
flavonoids reported to possess antioxidant activity.(1)” Sambucol® inhibits influenza A and B, HIV, and 
herpes simplex in vitro and in a randomized, placebo-controlled trial was associated with increased 
hemagglutination inhibition titers to influenza B infections in vivo.(1,2,6)   
A small study showed chimpanzees supplemented with prophylactic Sambucol® 10 ml once daily for 
approximately six months had less than 1/3 the days of flu-like symptoms compared with a placebo 
supplemented group. (7) When symptoms occurred the dosage was increased to 15 ml twice daily, and the 
duration of illnesses were twice as long in the placebo group compared to the Sambucol® supplemented 
group.(7)  
Another review of the antiviral properties of black elder products states, Sambucus nigra (black elder) 
flowers have been approved by Commission E of the German Federal Institute for Drugs and Medical 
Devices for the treatment of viral infections, but other parts of the plant have not.  While the fruit is not 
on the FDA GRAS (generally recognized as safe, as the flowers are) list or approved by the German 
Commission E, analysis of flowers and cooked fruit have consistently indicated safety; other parts of the 
plant are less suitable for use.”(6)  Sambucol® uses only cooked fruit from the black elderberry plant. 
 

 
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1.4 Clinical Data to Date 
There are four published peer-reviewed randomized double-blind placebo-controlled clinical trials with 
relevance to the protocol under development.  Two, in 27 and 60 patients, demonstrated shortening of the 
duration of proven influenza by approximately 4 days with elderberry extract supplementation versus 
placebo (p<0.001 in both studies)(2,3)   
Another trial evaluated 64 patients with three or more of the following “flu-like symptoms”: fever, 
headache, muscle aches, coughing, nasal mucus discharge, and nasal congestion. (4) By 48 hours of 
supplementation, “9 patients (28%) in the elderberry extract supplemented group were void of all 
symptoms, 19 patients (60%) showed complete relief from some symptoms, and had only one or two mild 
symptoms” (1/10 on a visual analogue scale).  No patient in the placebo group achieved complete 
recovery, and only 5 patients (16%) showed improvement in one or two symptoms (p<0.001 for all 
symptoms).  Most patients in the placebo group remained the same or worsened over the 48-hour 
monitoring period.   
The fourth study of elderberry extract evaluated supplementation before, during and after air-travel in 312 
passengers.(8)  More cold episodes occurred in the placebo group (17 vs. 12) but that did not reach 
statistical significance (p=0.4).  “Placebo group participants had a significantly longer duration of cold 
episode days 117 vs.57, p=0.02) and the average symptom score over these days was also significantly 
higher (583 vs. 247, p=0.05).” 
A fifth study, by A. Rao and L. Vitetta, entitled “A prospective, double-blind, randomized, placebo-
controlled study to evaluate the safety and efficacy of a complementary medicine formulation, to help 
reduce duration and severity of cold and flu symptoms in otherwise healthy adults”, with a goal of 
enrolling 120 cold and 80 flu episodes, completed enrollment in Australia on 5/22/2017.  Preliminary 
results shared by Qayyum Adil, Ph.D. of PharmaCare® in Australia were, “Cold and Influenza relief: 
cold and influenza duration reduced by 30% (3 day equiv). Symptom severity 35% reduction (participants 
felt better, faster) using 15mL 4x daily.”   
1.5 Dose Rationale and Risk/Benefits  
The route of administration, dosage, dosage regimen, and dosage period rationale is based upon two 
previous studies using Sambucol® supplementation for influenza. (2, 3). Sambucol® supplementation 
decreased duration of symptoms by approximately 4 days.  The only side effect reported in these studies 
was bad taste in one patient.  The only reported side effects in the 312 air travelers study were 3 placebo 
patients each with one symptom, either itchy throat, fatigue, or kidney pain, and 2 elderberry patients, one 
with fatigue and one with cold symptoms.   Also, there have been twenty-six years of clinical experience 
with Sambucol® as an over-the-counter supplement now available on six continents, with 21 years 
availability in the United States.  There are no reported serious adverse effects, and dosage 
recommendations outside the United States are available for ages 2 and above 
(http://www.cpginteractive.com/sam/faqs.html) and for ages 5 and above in the United States.  Subjects’ risks 
under this protocol are minimal, and the potential benefits to the subjects and society are great.  
 
2 STUDY OBJECTIVES 
Determine if elderberry extract supplementation shortens the duration and decreases the severity of 
influenza symptoms in patients who have been prescribed or offered a prescription of oseltamivir or 
baloxavir marboxil (Xofluza) for documented influenza infection. 
 

 
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3 STUDY DESIGN 
3.1 General Design 
This is a Phase IV randomized, double-blind, placebo-controlled trial of elderberry extract 
supplementation versus placebo.  Sixty-five to one hundred patients with RocheR cobasR LiatR polymerase 
chain reaction documented influenza, with at least 2 moderate influenza symptoms as defined below, and 
who have been prescribed or offered a prescription for oseltamivir or baloxavir marboxil will be 
randomized to also receive elderberry extract supplementation or placebo. 
3.2 Study Endpoints  
Baseline data will be obtained at time of presentation including eligibility criteria, medical history, and 
current influenza symptoms.   
Symptoms will be recorded using the scoring system described in a meta-analysis of “all published and 
unpublished Roche-sponsored randomized placebo-controlled, double-blind trials of oseltamivir treatment 
in adult influenza” (9).  “The primary outcome will be time to alleviation of all symptoms.  Seven 
influenza symptoms (nasal congestion, sore throat, cough, aches and pains, fatigue, headaches, and chills 
or sweats)” will be graded by severity as “absent” (0), “mild” (1), “moderate” (2), or “severe” (3).  
Alleviation will be defined to arise when all symptoms scored as absent or mild, and remain so for at least 
21.5 hours.”  The secondary endpoints will be the time to alleviation and to complete resolution of 
individual and all symptoms.   Patients will be followed daily until all symptoms have completely 
resolved and fever has remained less than 100° F for 24 hours, or for a maximum of 21 days if symptoms 
have not yet completely resolved for 24 hours. 
3.3 Primary Safety Endpoints   
The conditions or symptoms that will be recorded from day of presentation until influenza symptoms are 
resolved include; dry mouth, bad taste, nausea, vomiting diarrhea, constipation, abdominal pain,, rash, 
difficulty breathing, decreased drinking, dizziness and any other symptoms not previously recorded under 
study endpoints as outlined above.  Patient symptoms and severity of illness will be monitored daily using 
the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE 
GRADING TABLE).  See appendix one for all case report forms.  Study patients will be asked to call for 
any worsening influenza symptoms or new conditions or symptoms reaching Grade 3 or 4.  See also 
section 8 safety and adverse events. 
 
4 SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion Criteria  
Patients are eligible to be included in the study if they meet all of the following criteria: 
 
[1] Males or females ≥ 5 years of age 
[2] With 48 hours or less of an influenza illness documented by polymerase chain reaction 
[3] Have AT LEAST 2 of the following 7 influenza symptoms (nasal congestion, sore throat,   
cough, aches and pains, fatigue, headaches, and chills or sweats) graded as either moderate 
or severe 
[4] Have been prescribed or offered a prescription of oseltamivir or baloxavir marboxil (Xofluza) 

 
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[5] Have access to a phone 
[6] Subjects are capable of giving informed consent or have an acceptable legally authorized 
representative capable of giving consent on the subject’s behalf with informed assent given 
by subject. 
4.2 Exclusion Criteria  
Patients will be excluded from the study if they meet any of the following criteria: 
 
[1] Known allergy to elderberry extract, oseltamivir, or baloxavir marboxil (Xofluza) 
[2] Use of antibiotic or antiviral medication on presentation to the study  
[3] Women who are pregnant, breastfeeding women, or do not agree to appropriate 
contraception (abstinence, hormonal, intrauterine device, and barrier) to prevent pregnancy 
during the study. 
[4] Patients with HIV 
[5] Patients with cystic fibrosis 
[6] Patients currently taking Elderberry Extract or Sambucol 
 
4.3 Subject Recruitment and Screening 
Study personnel in the Main Campus, Hillcrest and Fairview emergency rooms will be notified of all 
positive influenza polymerase chain reaction testing obtained in the emergency rooms.  Study personnel 
will then screen these patients’ charts for eligibility.  Those patients interested in enrolling and willing to 
provide written informed consent will be enrolled in the study. 
At Main Campus, Hillcrest and Fairview Emergency Rooms handouts explaining the study and home 
management of influenza will be placed where the polymerase chain reaction testing is performed.  
Potentially eligible patients testing positive for influenza will be given a copy of the handout by study 
staff or staff ordering or performing test.   
The only laboratory testing required to meet inclusion criteria will be positive influenza rapid test 
polymerase chain reaction, and in women of childbearing potential a negative urine pregnancy test. 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Patients may withdraw from the trial at any time and for any reason.  Some possible reasons for early 
withdrawal include the following: 
 
Development of a medical condition or need for concomitant treatment that precludes further 
participation in the trial 
 
Unacceptable toxicity or any adverse event that precludes further participation in the trial 
 
The investigator removes the patient from the trial in the best interests of the patient 
 
Study completion or discontinuation 
 
Patient withdraws consent to continued participation in the trial 

 
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4.4.2  Data Collection and Follow-up for Withdrawn Subjects 
We will continue to collect data on subjects until they are well or for 21 days if they are not entirely well 
only if they agree to accept our follow-up phone calls.  We will call and leave messages three times 
before concluding a subject is truly lost to follow-up. 
 
5 STUDY SUPPLEMENT 
5.1 Description    
Thick reddish-brown liquid and each 15 ml of the oral liquid contains Sambucus Nigra (Black Elderberry) 
fruit juice equivalent to 5.7 grams. 
5.2 Supplement Regimen   
Patients will be given their randomly assigned study supplement and instructed to take 15 ml orally of 
medication, in measuring dispenser provided, four times a day for 5 days for ages 13 and above and 15 ml 
two times a day for ages 5-12 for 5 days. 
5.3 Method for Assigning Subjects to Supplement Groups 
Treatment assignment will be made by computer generated randomization with stratification based on age 
5-12 or 13 and above. 
 
5.4 Preparation and Administration of Study Medication 
Study active and placebo medications will be prepared by PharmaCare® in Australia and mailed in 120 
ml bottles with 2-3 bottles per patient of either Elderberry Extract or Placebo contained in boxes 
identifying the bottles in that box as either active or placebo medication.  
Medications will be stored in locked areas at room temperature in a storage area in the study     
emergency room area with temperature monitors and daily temperature logs.  Medications will be 
distributed by study personnel under the supervision of the Cleveland Clinic Investigational Pharmacy.  
The first dose of study medication will be administered by study personnel before the patients leave their 
presenting hospital.  Subsequent doses will be administered at home by patients and their families in 
study provided medicine dispensers used to measure proper dosage. 
5.5  Subject Compliance Monitoring 
Daily phone calls will monitor the patients’ symptoms, new medications or treatments, and compliance 
with the study medication regimen until reported complete resolution of patients’ symptoms for 24 hours, 
or after 21 days of the study, whichever occurs first. Patients requiring follow-up pregnancy tests will 
have the testing performed at the Cleveland Clinic laboratory of their choice.  Any patient who fails to 
comply with monitoring will be called three times in an effort to help with compliance with the study 
protocol.  Patients’ study medications and empty bottles remaining will be returned by stamped, 
addressed envelopes provided at the time of enrollment to the Main Campus based study coordinator.   At 
that time remaining medicine will be measured prior to disposal by the investigational pharmacy. 
5.6 Prior and Concomitant Therapy 
All medications taken at study enrollment will be recorded on the case report forms and then into 
REDCap Cloud, and any changes in medications will be recorded daily throughout the study. All patients 

 
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will be discouraged from taking any cold or flu preparations except for acetaminophen and ibuprofen as 
needed for pain and/or fever until they have completed the study and are completely well. 
5.7 Packaging 
Every study patient will be given two (for patients ages 5-12 years old) or three (for patients ages 13 and 
above) 120 ml bottles of their study medication labeled as below: 
 
Subject Name: _________________________ 
Subject Study Number:  _____ 
Contents:  120 ml of Elderberry Extract or Placebo  
Directions for use:  Ages 5-12:  Take 15 ml by mouth two times daily for five days 
                                 Ages 13 and above:  Take 15 ml by mouth four times daily for five days 
Protocol Title: Elderberry Extract or Placebo for Influenza 
Sponsor, Investigator name: Cleveland Clinic Foundation, Michael Macknin, MD 
Contact phone number, and address:  216-445-4876, 9500 Euclid Ave.  Cleveland, Ohio 44195 
Manufacturer:  PharmaCare Laboratories Pty Ltd 
Batch #:  TPA xxxxxxx/TPP xxxxxxx 
Expiration Date:  mm/yyyy 
Storage Conditions:  Store below 77oF 
Caution:  New Drug Limited by United States Law to Investigational Use 
 
5.8 Blinding of Study Medication  
A randomization scheme will be developed via computer algorithm with stratification by age (5 to 12 
years old and ≥13 years old). Investigational pharmacy personnel not involved in patient contact or data 
collection directly observed and supervised by the statistician will write the numbers on the appropriate 
bottles of medications.   
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Study Medication 
PharmaCare ®will ship the product to the Cleveland Clinic investigational pharmacy. 
Upon receipt of the study medication, an inventory will be performed and a medication receipt log filled 
out and signed by the investigational pharmacy personnel accepting the shipment. The investigational 
pharmacist will count and verify that the shipment contains all the items noted in the shipment inventory. 
Any damaged or unusable study supplement product in a given shipment will be documented in the study 
files. The investigator will notify study sponsor of any damaged or unusable study medication that were 
supplied to the investigator’s site. 
5.9.2 Storage 
There are no special storage or handling requirements.  All supplies will be stored at room temperature 
between 55-77° F locked in a designated storage area for each study site emergency room with 
temperature monitors and logs. 
5.9.3 Dispensing, Return, and Destruction of Study Medications 
Medications will be assigned and dispensed to each subject consecutively at the study site of enrollment.  

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
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At the completion of the study, participants are instructed to return by mail any used or unused study 
medication and Oseltamivir or baloxavir marboxil (Xofluza) to the CCF Main Campus. The study 
coordinator will perform a final reconciliation of medication dispensed, medication consumed, and 
medication remaining. This reconciliation will be logged in REDCap Cloud. Any discrepancies noted will 
be investigated, resolved, and documented prior to the destruction of any medication. All returned 
medications will be disposed of on site in accordance with Cleveland Clinic Pharmacy Disposition or 
Disposal of Investigational Drugs Policy and will be documented in the study files. 
 
6 STUDY PROCEDURES 
6.1 Pre-registration and Screening  
If patients are eligible and interested in participating we will review the informed consent with them, and 
their families if necessary, and obtain written informed consent or assent, depending upon patients’ ages. 
6.2 Visit 1  
Visit 1 will be completed at the same visit for registration and screening.   A nasopharyngeal swab will be 
obtained for RocheR cobasR LiatR PCR assays for influenza A&B prior to enrollment in study to confirm 
all study patients have documented influenza.  
Informed consent, and assent when indicated, will be obtained prior to completing any study related 
assessments. Eligibility for the study will be confirmed and baseline data will be obtained.   
All women of childbearing potential will have a urine pregnancy test before starting and upon completion 
of the study.  Pregnancy tests will be done following standard Cleveland Clinic operating procedures and 
documented in the electronic medical record, the case report forms and REDCap Cloud. The result of the 
pregnancy test(s) will be disclosed to the minor subject and their parent(s)/legal guardian.  
Patients will be instructed on how to return unused study medication in the provided stamped envelope 
addressed to the study coordinator, and for women of childbearing potential how to obtain an end of study 
pregnancy test at the most convenient Cleveland Clinic laboratory. 
Patients will be given their randomly assigned study medication and instructed to give 15 ml of 
medication, in a measuring cup provided, 4 times a day for 5 days for ages 13 and above and 15 ml 2 
times a day for ages 5-12 for 5 days.  They will be given their first dose of study medication prior to 
leaving the emergency room. 
Patients will be asked to please avoid taking any additional cold or influenza medications if possible.  
They will be told they may take ibuprofen or acetaminophen for pain or fever. They will be asked to 
report daily all medications taken not reported on their day 1 visit.  Taking additional medications will not 
disqualify patients from the study other than taking prescription antibiotics or antivirals prior to the start 
of the study. 
Patients will receive daily phone calls to remind them to take each dose of their study medication and to 
answer their daily surveys (see Appendix 1).  All patients who do not answer their daily surveys on the 
first call, will receive two additional phone call attempts to have the survey answered.  
 
6.3  Visit 2, etc.   
After the initial in-person study visit at the time of enrollment, all subsequent visits will be by telephone. 
As previously outlined, women of childbearing potential will have an end of study urine pregnancy test to 
be arranged at a nearby Cleveland Clinic Laboratory. 
 

 
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Study Assessments 
Procedure 
Screening/Baseline 
Visit One 
Daily 
Phone Call 
Until 
Well 
Final Study 
Visit 
Confirm Inclusion/Exclusion Criteria 
X 
 
 
Obtain Informed Consent 
X 
 
 
Nasopharyngeal swab for PCR test for 
influenza A&B, RSV 
X 
 
 
Urine Pregnancy Test for Women of 
Childbearing Potential 
X 
 
X 
Screening/Enrollment Questionnaire 
X 
 
 
Dispense Study Medication 
X 
 
 
Daily (Symptom) Questionnaire 
X 
X 
X 
Record Side Effects/AE/SAE 
 
X 
 
Study Drug Return 
 
 
X 
 
 
Laboratory Procedures 
RocheR cobasR LiatR PCR assays for influenza A&B and RSV on day of entry into study.  This is CLIA 
waived testing. 
Urine pregnancy testing initially will be done using a point of care pregnancy test per standard Cleveland 
Clinic procedures.  The end of study pregnancy testing will be done per usual protocol at Cleveland Clinic 
outpatient laboratories. 
 
7 STATISTICAL PLAN 
7.1 Sample Size Determination   
Duration of influenza was chosen as our primary outcome because previous studies described beneficial 
effects of elderberry extract  on this outcome (1-4) and published data is available on the elderberry 
extract manufactured by the company supplying elderberry extract for our study to use to calculate our 
sample size.(3)  Forty-six total influenza positive patients randomized at a 1:1 ratio with 23 active and 23 
placebo patients are needed for a power of 90% to detect a mean difference in duration of illness of at 
least two days with a Type I error rate of 0.05, assuming standard deviations of 1.3 and 2.5 days in the 
supplement and placebo groups respectively.(3)  Sixty-five to one hundred patients will be enrolled in our 
study.  We are assuming a cautious estimate of nearly a 30% dropout rate.  
7.2 Statistical Methods   
Study groups will be compared on duration of illness using a two-sample unequal variance t-test; the data 
will be transformed (such as by log-transformation) to meet distributional assumptions, and the mean 

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
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difference between groups with 95% confidence interval will be reported. Secondary analyses will assess 
the time to resolution of individual symptoms, and compare study groups on adherence to protocol and 
side effects using two-sample t-tests and Chi-square tests as appropriate. These analyses will be 
performed on an intent-to-treat basis. All tests will be two-tailed and performed at a significance level of 
0.05. SAS 9.4 software will be used for all analyses.   
7.3 Subject Population(s) for Analysis 
All-randomized population:  Any subject randomized into the study, regardless of whether they received 
study drug 
 
8 SAFETY AND ADVERSE EVENTS 
8.1 Definitions As Defined by Cleveland Clinic IRB-60 Adverse Event Reporting 
The Institutional Review Board requires Investigators to monitor and report Adverse Events. The 
Institutional Review Board is responsible to assess changes in risk to ensure safety protections of human 
subjects. 
An Unanticipated Problem Involving Risks to Participants or Others is any event that (1) is 
unforeseen, (2) caused harm or placed a person at increased risk of harm, and (3) is related to the research 
procedures. 
An Adverse Event (AE) is any untoward or unfavorable medical occurrence, including any abnormal 
sign (for example, abnormal physical exam or laboratory finding), symptoms, or disease. Adverse events 
can encompass both physical and psychological harms. 
An Internal Adverse Event (AE) is an untoward medical occurrence, which occurs to participants in 
research conducted by Cleveland Clinic and/or Cleveland Clinic is the IRB of record. 
A Serious Adverse Event (SAE) is any adverse experience that results in any of the following outcomes: 
o death 
o a life-threatening experience 
o inpatient hospitalization or prolongation of existing hospitalization 
o a persistent or significant disability/incapacity 
o a congenital anomaly/birth defect 
o Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 
based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
An Unexpected Adverse Event means any AE not previously known or included in the current 
Investigator’s Brochure, consent form or other risk information. 
Related/Possibly Related means there must be reasonable evidence to suggest the event was caused by 
the drug, device or investigational intervention. 

 
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8.2 Recording of Adverse Events 
At each daily contact, using questionnaires in Appendix 1,the investigator will seek information on 
adverse events  detailing any Grade 1 through 4 DAIDS side effects as defined in Section 14.1, pages 24-
25. Patients will be instructed to contact the study personnel at 216-445-4876  for all suspected  Grade 3 
or 4 side effects (First calling 911 for Grade 4 side effects and contacting study personnel once able) 
Patients will then be triaged as appropriate to their primary medical provider or urgent or emergency care 
facilities.  Information on all adverse events will be recorded immediately in the source document, and 
also in the appropriate adverse event section of the case report form (CRF).  All clearly related signs, 
symptoms, and abnormal diagnostic procedures results will also be recorded in the source document.  
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious adverse events that are still 
ongoing at the end of the study period will be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation will be recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events 
A serious adverse event will be reported to the study investigator/sponsor by telephone within 24 hours of 
the event.  A Serious Adverse Event (SAE) form must be completed by the investigator and faxed to the 
study sponsor, Dr. Michael Macknin within 24 hours. The investigator will keep a copy of this SAE form 
on file at the study site.  Report serious adverse events by phone and facsimile to: Michael Macknin 216-
445-4876, 216-445-3523 respectively.   
At the time of the initial report, the following information will be provided: 
 
Study Identifier 
 
Study Center 
 
Subject Number 
 
A description of the event 
 
Date of onset 
 
Current Status 
 
Whether study supplement was discontinued 
 
Reason why the event is classified as serious 
 
Investigator assessment of the association between the event and study treatment 
 
Significant new information on ongoing serious adverse events will be provided promptly to the study 
sponsor. 
8.3.1 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) will be submitted to the CCF IRB 
per the guidelines located in the CCF IRB Standard Operating Procedures under IRB-60 in manual. 
Copies of each report and documentation of IRB notification and response will be filed in the regulatory 
binder. 
The following four types of events will be reported to the Cleveland Clinic IRB:  

 
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1. Adverse events which are serious, unexpected, and related or possibly related to participation 
in the research.  
2. Serious adverse events that are expected in some subjects, but are determined to be occurring 
at a significantly higher frequency or severity than expected.  
3. Other unexpected adverse events, regardless of severity, that may alter IRB analysis of the 
risk versus potential benefit of the research and, as a result, warrant consideration of 
substantive changes in the research protocol or informed consent process/document.  
4. Unanticipated Problems involving risks to subjects or others or any serious or continuing 
noncompliance with this policy or the requirements or determinations of the IRB.” 
8.3.2 FDA Notification by Sponsor (if applicable) 
The study investigator/sponsor shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the supplement as soon as 
possible but no later than 7 calendar days from the sponsor’s original receipt of the information. 
If a previous adverse event that was not initially deemed reportable is later found to fit the criteria for 
reporting, the study sponsor will submit the adverse event in a written report to the FDA as soon as 
possible, but no later than 15 calendar days from the time the determination is made. 
8.4 Unblinding Procedures 
The safety of the subject always comes first, we will seriously consider if unblinding the study therapy is 
necessary to ensure a subject’s safety. If unblinding study supplement on a subject is deemed necessary, 
the study biostatistician will unblind the subject and documentation of this in the subject’s source 
document will be completed.   In most cases, the unblinding will be part of managing an SAE, and will be 
reported with the SAE, however, in cases where unblinding was not associated with an SAE, such actions 
should be reported in a timely manner. We will use the same timeline requirements for investigator 
reporting of SAEs, (notification of sponsor within 24 hours by phone or fax, followed by a written 
narrative of the event within 48 hours.) 
8.5 Stopping Rules 
Stopping rules will not be used in this study. 
8.6 Medical Monitoring 
The Principal Investigator and Monitor will oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-monitoring plan (see section 9 
Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
8.7 Criteria for Withdrawal of Patient from Study.  
Patients may choose to withdraw from the study at any time. 
Patients with DAIDS Grade 4 symptoms, felt to be due to a study medication side effect by their 
physician of record, will be withdrawn from the study with ongoing follow-up of symptoms until the 
patient’s acute symptoms resolve. 
If patients become too ill to tolerate oral study medication they will be withdrawn from the study with 
ongoing follow-up of symptoms until the patient’s acute symptoms resolve.  

 
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If patients develop an allergy to study medication or become pregnant during the study they will be 
withdrawn from the study with ongoing follow-up until their acute symptoms resolve. 
 
9 DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality and Privacy 
Information about study subjects will be kept confidential and managed according to the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject 
authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke authorization for use of PHI.  
The required HIPAA language for subject authorization (included as part of the informed consent form) 
as found in the CCF IRB consent form template.  
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documentation. Examples include but are not limited to: original documents, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, copies or transcriptions of electronic records certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy and laboratories, etc.  
9.3  Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study (in hard copy or 
electronic format). All data requested on the CRF must be recorded in EPIC as the source document. 
9.4  Records Retention 
The investigator will retain study essential documents for 6 years with the source documents in EPIC 
being retained indefinitely. 
 
10 STUDY MONITORING, AUDITING AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities deemed necessary. The 
Investigator will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all study-related documents and study related facilities (for example, pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit.” 

 
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10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and Institutional compliance and quality assurance groups of all study 
related documents (for example, source documents, regulatory documents, data collection instruments, 
study data etc.). The investigator will ensure the capability for inspections of applicable study-related 
facilities (for example, pharmacy, diagnostic laboratory, etc.). Participation as an investigator in this study 
implies acceptance of potential inspection by government regulatory authorities and applicable 
Institutional compliance and quality assurance offices. 
 
11 ETHICAL CONSIDERATIONS 
This study will be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor [if applicable] before 
commencement of this study. The investigator should provide a list of IRB members and their affiliate to 
the sponsor. 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision  
 
12 PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study 
is obligated to provide the sponsor with complete test results and all data derived from the study.  Note:  
Sponsor is Investigator 
 
13 REFERENCES 
 
1. Ulbricht C, Basch E, Cheung L, et al.  An evidence-based systematic review of elderberry and 
elderflower (Sambucus nigra) by the Natural Standard Research Collaboration.  Journal of Dietary 
Supplements  2014;11(1):80-120 
2. Zakay-Rones Z, Varsano N, Zlotnik M, et al. Inhibition of several strains of influenza virus in vitro 
and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during and outbreak of 
influenza B Panama. The Journal of Alternative and Complementary Medicine 1995;1(4):361-36 
3. Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized study of the efficacy and safety of oral 
elderberry extract in the treatment of influenza A and B virus infections. The Journal of International 
Medical Research 2004;32:132-140 

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
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4. Kong F. Pilot study on a proprietary elderberry extract: efficacy in addressing influenza symptoms. 
Online Journal of Pharmacology and PharmacoKinetics 2009;5:32-43 
5. Disease Burden of Influenza|Seasonal Influenza (Flu)|CDC   
www.cdc.gov/flu/about/diseaseburden.htm  updated 5/16/17 
6. Porter RS, Bode RF.  A Review of the Antiviral Properties of Black Elder (Sambucus nigra L.) 
Products. Phytotherapy Research 2017;31:533-554 
7. Burge B, Mumcuoglu M, Simmons T.  The effect of Sambucol on flu-like symptoms in chimpanzees:  
prophylactic and symptom-dependent treatment.  International Zoo News 1999;46:  16-19 
8. Tiralongo E, Wee SS, Lea RA. Elderberry supplementation reduces cold duration and symptoms in 
air-travelers: a randomized double-blind placebo controlled-clinical trial. Nutrients 2016;8, 182; 
doi:10.3390/nu8040182 
9. Dobson J, Whitley RJ, Pocock S, Monto AS.  Oseltamivir treatment for influenza in adults: a meta-
analysis of randomized controlled trials.  Lancet 2015;385:1729-1737  
10. People at High Risk of Developing Flu-Related Complications 
www.cdc.gov/flu/about/disease/high_risk.htm updated 8/25/16 
 
 
14 ATTACHMENTS    
14.1 Screening/Enrollment Questionnaire 
 
SCREENING/ENROLLMENT QUESTIONNAIRE 
 
Inclusion Criteria  
Mark if Yes 
1) ____Patients ages 5 and above  
2) ____With 48 hours or less of an influenza illness documented by polymerase chain reaction 
3) ____ Have AT LEAST 2 of the following 7 influenza symptoms (nasal congestion, sore throat,     
cough, aches and pains, fatigue, headaches, and chills or sweats) graded as either moderate or 
severe 
4) ____Who have been prescribed or offered a prescription for oseltamivir or baloxavir marboxil 
5) ____Who have access to a phone  
6) _____Subjects are capable of giving informed consent or have an acceptable legally authorized 
representative capable of giving consent on the subject’s behalf with informed assent given by 
subject. 
 
Exclusion Criteria (mark if NO) 
1. ____ Known allergy to elderberry extract, oseltamivir or baloxavir marboxil 
2. ____ Use of antibiotic or antiviral medication on presentation to the study  
3. ____ Pregnant women 
4. ____ Breastfeeding women 

 
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5. ____ Women who do not agree to appropriate contraception (abstinence, hormonal, intrauterine 
device, and barrier) to prevent pregnancy during the study. 
6. ____ Patients with HIV  
7. ____ Patients with cystic fibrosis  
____ CHECK HERE TO CONFIRM ALL ABOVE ARE NEGATIVE 
____ CHECK HERE TO CONFIRM URINE PREGNANCY TEST NEGATIVE IF 
APPLICABLE 
 
Additional Information Recorded on All Patients at the Time of Enrollment 
Study number   _____ 
Birth Date         _____ 
Sex 
 
_____ 
Race 
 
_____ 
Tobacco use 
_____ 
Allergies 
_____ 
 
High Risk Criteria 
Patients considered at high risk from influenza (10)  
Mark if Yes, Leave Blank if No, then Circle or Write-in specific illness*****IF More than one 
possible Answer 
1. ____ Adult 65 years of age and older 
2. ____ Resident of nursing homes and other long-term care facilities 
3. ____ American Indian or Alaskan Native*****  
People who have medical conditions including: 
4. ____ Asthma 
5. ____ Neurological and neurodevelopmental conditions [including disorders of the brain, spinal 
cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy (seizure disorders), stroke,  
muscular dystrophy, or spinal cord injury].***** 
6. ____ Chronic lung disease (such as chronic obstructive pulmonary disease [COPD])***** 
7. ____ Heart disease***** 
8. ____ Blood disorders (such as sickle cell disease) ***** 
9. ____ Endocrine disorders (such as diabetes or thyroid) ***** 
10. ____ Kidney disorders***** 
11. ____ Liver disorders***** 
12. ____ Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)***** 
13. ____ Weakened immune system due to disease or medication (such as people with cancer, or those 
on 20 mg/day of prednisone or more for more than 14 days)*****    
14. ____ People younger than 19 years of age who are receiving long-term aspirin therapy 
15. ____ People with extreme obesity (body mass index [BMI] of 40 or more) 
 
PLEASE LIST ALL MEDICATIONS AND DOSAGES AND HOW OFTER YOU TAKE THE 
MEDICINE.  PLEASE INCLUDE PRESCRIPTION AND OVER-THE-COUNTER 
MEDICATIONS INCLUDING IBUPROFEN (MOTRIN, ADVIL), ACETAMINOPHEN 
(TYLENOL), COLD AND FLU PREPARATIONS, AND HERBAL AND OTHER 
COMPLEMENTARY MEDICATIONS, VITAMINS, MINERALS AND SUPPLEMENTS 
_____________________________________________________________________________________
_____________________________________________________________________________________

 
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_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
All other medical illnesses not previous recorded 
_____________________________________________________________________________________ 
 
_____________________________________________________________________________________ 
Influenza vaccine status up to date YES_____NO_____ 
If NO and <9 y.o. was one vaccine given this year YES____NO____ 
Weight at day of presentation_____ 
Highest measured temperature during day of presentation_____ 
 
Symptom Score (9):  
0=NONE or Baseline 
1=MILD 2=MODERATE 3=SEVERE    
 
 
 
 
Nasal congestion            _____ 
Sore throat 
             _____ 
Cough  
 
_____ 
Aches and pains             _____ 
Fatigue                           _____ 
Headaches  
 
_____ 
Chills and sweats 
_____ 
 
 
Symptoms are graded by severity as “absent” (0), “mild” (1), “moderate” (2), “severe” (3)   
Presence or absence of possible other conditions or symptoms  at baseline AND their severity:   
 
SYMPTOM                    
SEVERITY OF SYMPTOM 
NONE=0   MILD=1   MODERATE=2   SEVERE=3  
BAD TASTE  
 
____ 
DRY MOUTH  
 
____ 
ABDOMINAL PAIN  
____ 
NAUSEA 
 
 
____ 
VOMITING 
 
 
____ 
DIARRHEA 
 
 
____ 
CONSTIPATION 
 
____ 
DIZZINESS 
 
 
____ 
HEADACHE   
 
____ 
RASH  
 
 
____ 
DIFFICULTY BREATHING ____ 
DECREASED DRINKING 
____ 
LIST ANY OTHERS WITH SEVERITY OF ANY SYMPTOM 
            
____________________________________________________________ 
____________________________________________________________ 
 
VITAL SIGNS IN EMERGENCY ROOM, N/A IF ALL NOT AVAILABLE 
 
______ TEMPERATURE 0F 
 ______ WEIGHT 

 
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______ PULSE 
______ RESPIRATORY RATE 
______ BLOOD PRESSURE 
______ PULSE OXIMETRY 
ABNORMAL PHYSICAL EXAMINATION FINDINGS, N/A IF ALL NOT AVAILABLE 
GENERAL APPEARANCE______________________________________________________________ 
SKIN________________________________________________________________________________
LYMPH______________________________________________________________________________
HEENT______________________________________________________________________________ 
CHEST______________________________________________________________________________
COR________________________________________________________________________________ 
ABD________________________________________________________________________________ 
GENIT_______________________________________________________________________________ 
NEUROMUSC________________________________________________________________________ 
 
 
In addition, every day patients are in the study starting from the first contact to the first day they are back 
to their baseline symptom level they will be asked to use the Division of AIDS (DAIDS) scale for grading 
the severity of adult and pediatric adverse events version 1.0, December 2004: clarification August 2009. 
Unlike the Symptom Score above, there are specific definitions of Grades 1-4 as outlined below.  
 
Grade 1 Mild is defined as “Symptoms causing no or minimal interference with usual social & functional 
activities”.   
Grade 2 Moderate is defined as “Symptoms causing greater than minimal interference with usual social 
and functional activity”.  
Grade 3 Severe is defined as “Symptoms causing inability to perform usual social and functional 
activity”.   
Grade 4 Potentially Life-Threatening is defined as “Symptoms causing inability to perform basic self-care 
functions OR medical of operative intervention indicated to prevent permanent impairment, persistent 
disability or death”.   
The patients will be asked to call immediately the study personnel mobile phone at 216-445-4876 for any 
suspected side effects at Grades 3. These patients will be referred by the principal investigator to their 
primary care physician, or urgent or emergency care facilities as appropriate with follow-up of their acute 
symptoms by the principal investigator or study coordinators until these symptoms resolve.   
 
ATTENTION 
PATIENTS WILL BE TOLD TO CALL 911 FOR ALL GRADE 4 SYMPTOMS.  After their health 
care needs are met for Grade 4 symptoms we will ask that they please call study line for follow-up and 
study personnel will also keep in touch with them daily until they are well. 
  
WRITE TIME_____AM or PM AND DATE ____ OF FIRST HAVING 2 
MODERATE SYMPTOMS OF INFLUENZA 
TIME_____AM or PM AND DATE_____ FIRST DOSE OF STUDY 
MEDICATION GIVEN AT ENROLLMENT 
Guess after first dose of medication if receiving:  Elderberry __OR 
Placebo_____ 

 
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_____  CHECK TO CONFIRM PATIENTS TOLD TO KEEP ALL EMPTY AND/OR 
PARTIALLY FILLED STUDY MEDICATION, OSELTAMIVIR (TAMIFLUR), OR BALOXAVIR 
MARBOXIL (XOFLUZA)  BOTTLES FOR THE FINAL STUDY VISIT AND RETURN OF UNUSED 
MEDICINE IN POSTAGE PAID ENVELOPES PROVIDED AT ENROLLMENT.  RECORD GUESS 
IF GIVEN ACTIVE OR PLACEBO MEDICATION 
14.2 Daily (Symptom) Questionnaire 
 
DAILY (SYMPTOM) QUESTIONNAIRE 
 
 
SYMPTOMS QUESTIONNAIRE (PLEASE NOTE IF SYMPTOM USUALLY PRESENT, SUCH 
AS A RUNNY NOSE WITH NASAL ALLERGIES, CONSIDER THAT BASELINE LEVEL OF 
SYMPTOM AS SYMPTOM BEING NONE, AND EACH SUBSEQUENT LEVEL A 
PROGRESSIVELY HIGHER LEVEL) 
 
 
SYMPTOM SCORE SYMPTOMS WRITE NUMBER                
SYMPTOM SEVERITY 
NONE=0   MILD=1   MODERATE=2   SEVERE=3 
 
NASAL CONGESTION 
____ 
SORE THROAT                       ____ 
COUGH 
 
 
____ 
ACHES AND PAINS                ____ 
FATIGUE                                  ____ 
HEADACHES  
 
____ 
CHILLS OR SWEATS            ____ 
 
 
 
 
 
 
HIGHEST MEASURED TEMPERATURE IN PAST 24 HOURS _____ 
IF TODAY IS THE FIRST DAY OF ILLNESS THAT ALL SYMPTOMS ABOVE ARE NONE 
OR MILD AND THEY HAVE BEEN ALLEVIATED FOR 21.5 HOURS, PLEASE RECORD THE 
BEST GUESS OF THE TIME THIS ALLEVIATION OF ALL SYMPTOMS OCCURRED   
BEST GUESS OF TIME ALL SYMPTOMS HAD BEEN NONE OR MILD FOR 21.5 HOURS 
TIME   _____AM or PM        DATE _____ 
 
POSSIBLE NEW CONDITIONS OR SYMPTOMS QUESTIONNAIRE  
 
 
SYMPTOM                                                       SEVERITY OF SYMPTOM 
                                                               NONE=0   MILD=1   MODERATE=2   SEVERE=3 
 
BAD TASTE  
 
____ 
DRY MOUTH  
 
____ 
ABDOMINAL PAIN  
____ 
NAUSEA 
 
 
____ 
VOMITING 
 
 
____ 
DIARRHEA 
 
 
____ 
CONSTIPATION 
 
____ 

 
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DIZZINESS 
 
 
____ 
HEADACHE   
 
____ 
RASH  
 
 
____ 
DIFFICULTY BREATHING ____ 
DECREASED DRINKING 
____ 
LIST ANY OTHERS WITH SEVERITY OF ANY SYMPTOM 
            
____________________________________________________________ 
____________________________________________________________ 
 
TOTAL NUMBER OF DOSES OF STUDY MEDICATION TAKEN TODAY _____ 
TOTAL NUMBER OF DOSES OF OSELTAMIVIR (TAMIFLUR) OR BALOXAVIR 
MARBOXIL (XOFLUZA) TAKEN TODAY_____ 
PATIENTS TOLD TO KEEP STUDY MEDICATION AND OSELTAMIVIR OR BALOXAVIR 
MARBOXIL EMPTY, PARTIALLY FILLED, OR FULL BOTTLES FOR MAILING IN 
STAMPED ADDRESSED ENVELOPE PROVIDED _____  
REVIEWED PROPER DISPOSAL OF STUDY MEDICATION BY MAILING BACK IN 
STAMPED ADDRESSED ENVELOPE PROVIDED AT TIME OF ENROLLMENT_____  
 
PLEASE LIST ALL MEDICATIONS AND NUMBER OF DOSAGES AND DOSE TAKEN 
TODAY EXCEPT FOR USUAL DAILY MEDICATIONS REPORTED AT START OF STUDY.  
PLEASE INCLUDE OVER-THE-COUNTER MEDICATIONS SUCH AS IBUPROFEN 
(MOTRIN, ADVIL), ACETOMINOPHEN (TYLENOL), COLD AND FLU PREPARATIONS, 
AND HERBAL AND OTHER COMPLEMENTARY MEDICATIONS, VITAMINS, MINERALS, 
DIETARY SUPPLEMENTS AND NEW PRESCRIPTION MEDICATIONS. 
 
PLEASE NOTE REASON(S) THESE NEW MEDICATIONS WERE STARTED  
 
In addition, every day patients are in the study starting from the first contact to the first day they 
are back to their baseline symptom level they will be asked to use the Division of AIDS (DAIDS) 
scale for grading the severity of adult and pediatric adverse events version 1.0, December 2004: 
clarification August 2009. Unlike the Jackson Score above, there are specific definitions of Grades 
1-4 as outlined below.  
 
Grade 1 Mild is defined as “Symptoms causing no or minimal interference with usual social & 
functional activities”.   
Grade 2 Moderate is defined as “Symptoms causing greater than minimal interference with usual 
social and functional activity”.  
Grade 3 Severe is defined as “Symptoms causing inability to perform usual social and functional 
activity”.   
Grade 4 Potentially Life-Threatening is defined as “Symptoms causing inability to perform basic 
self-care functions OR medical of operative intervention indicated to prevent permanent 
impairment, persistent disability or death”.   
The patients will be asked to call immediately to call the study personnel mobile phone at 216-445-
4876 for any suspected side effects at Grades 3. These patients will be referred by the principal 
investigator to their primary care physician, or urgent or emergency care facilities as appropriate 

 
Elderberry Extract in Patients with Influenza v.11-8-2018 
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with follow-up of their acute symptoms by the principal investigator or study coordinators until 
these symptoms resolve.   
PATIENTS WILL BE TOLD TO CALL 911 FOR ALL GRADE 4 SYMPTOMS.  After their 
health care needs are met for Grade 4 symptoms we will ask that they please call study line for 
follow-up and study personnel will also keep in touch with them daily until they are well.  
 
 
ON LAST DAY OF STUDY CONFIRM ALL SYMPTOMS RESOLVED 
AND TEMPERATURE (<1000F) FOR 24 HOURS AND ALSO RECORD: 
BEST GUESS OF EXACTLY WHEN ALL SYMPTOMS AND FEVER HAD BEEN RESOLVED 
FOR 24 HOURS   TIME_____AM/PM      DATE_____  
GUESS WHETHER STUDY MEDICATION WAS ELDERBERRY_____ OR PLACEBO______ 
WAS YOUR GUESS BASED MOSTLY BECAUSE OF: 
YOUR RESPONSE TO TREATMENT____ 
TASTE OF MEDICATION____  
OR SPECIFY SOMETHING ELSE_______________________________________ 
 
NUMBER OF BOTTLES OF STUDY MEDICATION REMAINING TO NEAREST ¼ ______ 
NUMBER OF BOTTLES TO NEAREST ¼ OR TABLETS OF OSELTAMIVIR (TAMIFLUR) OR 
BALOXAVIR MARBOXIL (XOFLUZA) REMAINING_____ 
CONFIRM STUDY MEDICATIONS REMAINING WILL BE MAILED IN STAMPED 
ENVELOPE PROVIDED AT ENROLLMENT ______ 
 
RESULTS OF PREGNANCY TESTING IN women of childbearing potential:  
POSITIVE_____NEGATIVE_____ 
 
ONCE MEDICATION RETURNED RECORD: 
ELDERBERRY EXTRACT OR PLACEBO REMAINING IN ML_____ 
OSELTAMIVIR OR BALOXAVIR MARBOXIL PILLS _____ OR ML_____ REMAINING 
 
 
 
 
 
 
 
 
14.3 Poster/Handout  
PLEASE NOTE:  APPENDIX 2 BELOW TO BE KEPT AT EMERGENCY ROOM INFLUENZA 
TESTING MACHINES TO BE DISTRIBUTED TO ALL PATIENTS WHO TEST POSITIVE 
FOR INFLUENZA. SIDE ONE WILL INCLUDE STUDY INFORMATION WITH INFLUENZA 
INFORMATION ON FLIP SIDE 

 
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Elderberry Extract in Patients with Influenza v.11-8-2018 
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14.4 Patient Take Home Checklist 
 
 

 
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