Rose Geranium in Sesame Oil Nasal Spray as an Agent to Improve Symptoms of Nasal Vestibulitis: A Phase III Double Blinded Randomized Controlled Trial
Phase: PHASE3
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Nasal Vestibulitis
Sponsor: Mayo Clinic

 
 
 
 
 
MC19C1 / 19-006677 
 
 
Rose Geranium in Sesame Oil Nasal Spray as an Agent to 
Improve Symptoms of Nasal Vestibulitis: A Phase III Double 
Blinded Randomized Controlled Trial 
 
 
NCT04620369 
 
 
Document Date: 05/19/2022 

MC19C1 
Protocol Version Date:19May2022 
 
 
Mayo Clinic Cancer Center 
 
MC19C1, Rose Geranium in Sesame Oil Nasal Spray as an Agent to Improve Symptoms of Nasal 
Vestibulitis: A Phase III Double Blinded Randomized Controlled Trial  
 
Sponsor/Principal Investigator: Charles L. Loprinzi, MD 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
507/284-2511 
 
Co-Principal Investigators  
Elizabeth Cathcart-Rake, MD  
 
 
Co-Investigators: 
Deanne Smith, APRN, MSN, CNP 
 
Susan Young, RN 
 
Bret Friday, MD  
 
MNCCTN Community Chair 
 
 
 
Karthik V. Giridhar, MD 
 
 
Kathryn J. Ruddy, MD 
 
Statistician: 
Paul Novotny, M.S. 
 
FDA IND #: 146082 
 
 
 
 
NCT04620369 
Drug Availability:  
Commercial Agents: Gateway Pharmacy; Bismark, ND 
 
 
MNCCTN institutions will enter patients on this clinical trial  
 
Document History 
(Effective Date) 
Activation  
November 13, 2020 
MCCC Amendment 1 
pending 
 
 
 
 
 
 
 
 
 

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Protocol Version Date:19May2022 
 
 
Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Jarek Moen, Data Manager or Quality Assurance Specialist 
Phone: 507/293-7339 
E-mail:moen.jarek@mayo.edu 
Drug administration, infusion pumps,  
nursing guidelines 
 
Susan Lewis-Peters, RN 
Phone: 507-266-1909 
E-mail: lewis.susan2@mayo.edu 
 
Protocol document, consent form, 
regulatory issues 
Angela Gosch, Sr. Research Protocol Specialist 
Email: Gosch.Angela@mayo.edu  
Serious Adverse Event Reporting 
Patricia G McNamara, SAE Coordinator 
Phone: 507/266-3028 
E-mail: RSTP2CSAES@mayo.edu  
*No waivers of eligibility allowed 
 
 

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Table of Contents 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 6 
3.0 
Registration Patient Eligibility ...................................................................................................... 6 
4.0  
Test Schedule ................................................................................................................................ 8 
5.0 
Stratification Factors ..................................................................................................................... 9 
6.0 
Registration/Randomization Procedures ....................................................................................... 9 
7.0 
Protocol Treatment ...................................................................................................................... 11 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 12 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 12 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 12 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 19 
12.0 
Descriptive Factors ..................................................................................................................... 19 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 19 
14.0 
Body Fluid Biospecimens: None ................................................................................................ 20 
15.0 
Drug Information ........................................................................................................................ 20 
16.0 
Statistical Considerations and Methodology ............................................................................... 21 
17.0  
Pathology Considerations/Tissue Biospecimens: None .............................................................. 27 
18.0 
Records and Data Collection Procedures .................................................................................... 27 
19.0  
Budget ......................................................................................................................................... 27 
20.0 
References ................................................................................................................................... 28 
Appendix I.  Baseline Pre-nasal Spray Questionnaire ................................................................................ 29 
Appendix II. Nasal Symptom and Patient Experience Questionnaire ........................................................ 31 
Appendix III PATIENT INFORMATION SHEETS .................................................................................. 33 
 
.

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle length= 14 days 
 
Generic name: Nasal Rose Geranium in Sesame Oil 
Brand name(s): N/A 
Availability: Gateway Pharmacy 
Generic name: Nasal Isotonic Saline 
Brand name(s): N/A 
Availability: Gateway Pharmacy 
Randomization 
Nasal Rose 
Geranium in 
Sesame Oil
Nasal Isotonic 
Saline 
Complete 
questionnaires 
weekly x 2  
Unblind and Cross-Over 
to active therapy, 
complete new baseline 
questionnaire.  Complete 
questionnaires weekly x2 
Complete 
questionnaires 
weekly x 2  
Unblind: End 
of treatment 
End of 
treatment 

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1.0 
Background  
Dryness, crusting, pain, and bleeding of the nostrils due to inflammation, termed nasal 
vestibulitis, is infrequently reported in the literature as a side effect of cancer-directed 
therapy, but recent reports support that this is a common clinical problem for which 
patients desire an effective intervention. One retrospective study described 115 patients 
who developed nasal vestibulitis while undergoing targeted therapy (1). Recently, a 
Mayo study surveyed 100 patients, who had undergone at least 6 weeks of cancer-
directed therapy, regarding the presence of nasal symptoms (2). Forty-one percent of the 
100 surveyed patients reported nasal symptoms, including dryness, pain, bleeding, and 
scabbing. Higher frequencies were reported among those who had received taxanes 
(71%), and VEGF-related therapies (78%).  
 
The current literature does not guide providers as to how best to treat nasal vestibulitis. 
Topical antibiotics may offer some benefit for nasal vestibulitis associated with cancer-
directed therapy. Of the 115 patients undergoing targeted therapy and evaluated by Ruiz 
et al, 95% of patients were treated with topical or oral antibiotics by a dermatology 
provider, and 60% reported symptom resolution (1), but this has not been prospectively 
studied.  
 
Another potential therapy for nasal vestibulitis is rose geranium in sesame oil nasal spray. 
This compound was initially evaluated in a small study, which showed that it decreased 
epistaxis severity among patients with hereditary hemorrhagic telangiectasia (2-4). After 
rose geranium in sesame oil nasal spray was anecdotally noted to improve nasal 
vestibulitis symptoms, a retrospective evaluation of its potential benefit in breast cancer 
patients undergoing cancer-directed therapy at Mayo Clinic was conducted. Of the 20 
patients who used the nasal spray product and responded to surveys, all reported 
symptomatic benefit, and 8 (40%) reported dramatic or complete resolution of symptoms.  
 
While very rare cases of lipoid pneumonia have been reported after ingestions of large 
amounts of sesame oil, this compound was generally well tolerated; although two patients 
reported unpleasant effects:  one commented that it was “messy” and another noted that it 
left an “oily coating at the back of the throat” (5, 6). A prospective study of rose 
geranium in sesame oil nasal spray is needed to better determine the potential benefit of 
this compound.  
 
The current trial is designed to prospectively evaluate the utility of a rose geranium in 
sesame oil nasal spray for treating established nasal vestibulitis.  
 
Nasal isotonic saline has not been studied in nasal vestibulitis. Limited data report that 
nasal isotonic saline mildly improves symptoms of rhinosinusitis, but it is most 
efficacious when utilized as a part of high-volume nasal irrigation (7-9). While it is 
frequently used to treat dry nasal passages, isotonic saline nasal spray was used as a 
placebo control in a trial evaluating a sesame oil nasal spray for weather-related dry nasal 
mucosa (4). 
 
 

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1.1 
Treatment 
1.11. Dosing and scheduling of rose geranium in sesame oil nasal spray 
This trial will be an evaluation of rose geranium in sesame oil nasal spray versus nasal 
saline. Rose geranium in sesame oil nasal spray is a compounded preparation, containing 
0.2 mL (4 drops) of pharmaceutical grade rose geranium oil to 119.8 mL of 
pharmaceutical grade sesame oil and then put into 30mL bottles. This is the same 
compound that was used in the aforementioned study of patients with hereditary 
hemorrhagic telangiectasia (2). Isotonic nasal saline will contain 0.9% sodium chloride 
with benzalkonium chloride, as a preservative, in a 30 mL bottle.  
1.12 Treatment duration 
The therapy will be given for two weeks. This should give us adequate time to determine 
whether rose geranium in sesame oil nasal spray can decrease nasal vestibulitis.  
Following that two week period, participants taking the saline spray will be allowed to 
cross over to the other spray. Subjects may cross over within two weeks after completion 
of treatment and be on therapy for an additional two weeks  such a patient must still be 
receiving chemotherapy or within 2 weeks of the last chemotherapy dose,  at the time of 
crossover. 
2.0 
Goals  
2.1 
Primary Goal 
To determine the ability of rose geranium in sesame oil nasal spray to alleviate nasal 
vestibulitis in patients undergoing systemic, antineoplastic therapy when compared with 
isotonic nasal saline.  
2.2 
Secondary Goals 
To assess toxicities related to rose geranium in sesame oil nasal spray in this study 
situation.  
3.0 
Registration Patient Eligibility 
3.1 
Registration - Inclusion Criteria 
3.11 
Age ≥18 years and be diagnosed with cancer and receiving chemotherapy 
3.12 
Ability to provide informed consent 
3.13  
Willingness to complete questionnaires 
3.14 
ECOG Performance Status (PS) 0, 1, 2 
3.15 
One or more of the following nasal symptoms for which the patient reports 
they would appreciate treatment. Symptoms must have started after the 
initiation of systemic, antineoplastic therapies, be attributed to the systemic, 
antineoplastic therapies, and symptoms must be reported  as being moderate 
(corresponding to a score of 2) or worse on a scale from mild (1) to very severe 
(4) on at least one of the items below.  
 
a. Dryness 

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b. Discomfort/Pain 
 
c. Bleeding 
 
d. Scabbing 
 
e. Sores 
3.2 
Registration - Exclusion Criteria 
3.21 
Predisposition to epistaxis prior to the initiation of cancer-directed therapy (more 
than once a month over the previous year). 
3.22 
Planned initiation or continuation of any topical nasal treatment other than the 
studied nasal spray,(such as nasal steroids, Ayr nasal gel, Neosporin ointment or 
nasal administration of petroleum jelly).  Taking Imitrex for migraines is 
acceptable. 
3.23 
Previous exposure to rose geranium in sesame oil nasal spray. 
3.24 
Concurrent upper respiratory tract infection 
3.25  
History of allergic or other adverse reactions to sesame oil or essential rose 
geranium oil 
3.26  
Any other reason that the study clinician or investigator feels precludes safe or 
appropriate inclusion in this study 
3.27  
Vulnerable populations: pregnant women, prisoners, mentally handicapped. 
3.3  
Re-Registration:  
3.31 
The patient will be un-blinded and determined to have been on the saline arm, 
when initially randomized. 
 

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4.0  
Test Schedule 
 
Active Monitoring Phase 
Tests and procedures 
≤ 14 days 
prior to 
Registration 
Baseline 
(Day 1) 
Days 7 and 14 
Window 
 
 
±3 days 
History and appropriate 
physical exam  
X 
 
 
Adverse event assessment 
 
X 
X 
Baseline pre-nasal spray 
questionnaire (App I) 
 
X2 
 
Nasal symptom and patient 
experience questionnaire (App 
II). Nurse should ensure that 
this  contains a record of 
patient’s most prominent nasal 
symptom at baseline 
 
 
X 
Nurse/research staff call1 
 
 
X 
1.  Phone evaluation once weekly, to remind patients to complete questionnaires and 
evaluate AEs. 
2.  Administer questionnaire on the same day nasal spray starts, making sure that the 
patient completes the questionnaire prior to receiving the study spray 
 
 
Cross-Over Continuation Phase (For Initial Saline participants only) 
Tests and procedures 
Baseline (Day 1) Days 7 and 14 after cross-
over 
Window 
±14 days 
± 3 days 
Patient contact (Nurse 
visit/call)  
X 
 
Adverse event assessment 
 
X 
Baseline pre-nasal spray 
questionnaire (App I) 
X2 
 
Nasal symptom and patient 
experience questionnaire 
(App II). Nurse/research 
staff should ensure that this 
contains a record of 
patient’s most prominent 
nasal symptom at baseline 
 
X 
Nurse/research staff call1 
 
X 
1. Phone evaluation once weekly, to remind patients to complete questionnaires and 
evaluate AEs 
2. Administer questionnaire on the same day nasal spray starts, making sure that the 
patient completes the questionnaire prior to receiving the study spray 
 
4.1 
Survival Follow-up: N/A 

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5.0 
Stratification Factors  
5.1 Gender: Male vs. Female 
5.2 Age: ≤ 50 vs. > 50  
5.3 History of Seasonal Allergies and/or Asthma: Yes vs. No 
6.0 
Registration/Randomization Procedures 
6.1 
Registration Procedures 
To register a patient, access the Registration Application at registration.mayo.edu. 
The Registration Application is available 24 hours a day, 7 days a week. If unable to 
access the application, contact the Mayo Clinic Site Management Team 
(ResearchSiteManagement@mayo.edu, 507-284-2753) between the hours of 8am 
and 4:30pm Central Time, Monday through Friday.  
 
Prior to initiation of protocol treatment, this process must be completed in its 
entirety and a MCCC Subject ID number (R######) must be assigned. It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  
 
All Institutions: 
6.2 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
507-284-0885). If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.5 
Baseline symptoms 
Only nasal symptoms are required to be documented at baseline, within one day prior to 
starting the spray.  
6.6 
Study drug 
Study agent will have been sent to the institution entering the patient. 

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6.7 
Patient questionnaire booklets  
Patient questionnaire booklets are available on site. Copies are not acceptable for these 
submissions. Booklets should be ordered using the Patient Questionnaire Order Form 
6.8 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files 
should be established at the beginning of the study, maintained for the duration of the 
study and retained according to the appropriate regulations. 
6.9 
Randomization Procedures  
6.9a1 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
6.9a2  After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups saline vs rose geranium in sesame oil using the Pocock and 
Simon dynamic allocation procedure which balances the marginal distributions 
of the stratification factors between the treatment groups (Pocock-Simon ref – 
see below).  
Procedures for Double Blinding the Treatment Assignment 
After the treatment assignment has been ascertained by the 
registration/randomization application, the patient’s study medication code 
number will be displayed on the confirmation of registration screen. 
 
MCCC Registration Office personnel will monitor the supply of coded bottles at 
each participating institution and will arrange for the research pharmacist to send 
further supplies to the participating institutions as needed. 
 
6.9b 
Crossover Registration (Step 2)  
To register a patient, access the Registration Application at registration.mayo.edu. The 
Registration Application is available 24 hours a day, 7 days a week. If unable to access 
the application, contact the Mayo Clinic Site Management Team 
(ResearchSiteManagement@mayo.edu, 507-284-2753) between the hours of 8am and 
4:30pm Central Time, Monday through Friday.  
 
Prior to initiation of protocol treatment, this process must be completed in its entirety.. It 
is the responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  
6.9b3    Treatment cannot begin prior to registering to the crossover phase and will 
ideally begin ≤14 days after registration for the crossover phase.  
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.12 
Treatment medication table 
Arm 
Agent 
Dose Level 
Route 
Days 
Cross-over 
continuation 
phase 
A 
Rose Geranium in 
Sesame Oil Nasal 
Spray 
1 spray into each 
nostril twice daily. 
One additional 
spray can be 
administered if the 
first spray is not a 
full spray 
Intranasal 
1-14 
twice daily 
N/A 
B 
Nasal Saline 
1 spray into each 
nostril twice daily. 
One additional 
spray can be 
administered if the 
first spray is not a 
full spray 
Intranasal 
1-14 
twice daily 
Administer 
the cross-
over nasal 
preparation, 
in the same 
manner as 
the first 
randomizati
on. 
Participants should not be taking other topical nasal preparations at the same time as the 
provided nasal sprays. If the patient develops a concurrent infection or allergic episode 
involving the nasal passages (i.e. sinusitis or allergic rhinitis) after enrollment, the 
treating physician should provide the appropriate treatment for this infection.  
7.2 
Breaking Codes in Double–Blinded Studies 
Emergency Unblinding Procedures  
In the event of an emergency, call the MCCC Registration Office at (507) 284–2753 to 
break the code on Monday through Friday, 8:00 a.m. to 4:30 p.m. Central Time. If the 
code must be broken after hours, assume the patient was assigned to active treatment and 
treat accordingly. Place a call to the MCCC Registration Office and leave a message 
informing them of the need to un-blind a patient. Provide your contact information so that 
MCCC Registration Office personnel can return the call the next business day. 
 
Protocol-Specific Unblinding Procedures 
Trial participants who complete initial protocol treatment may be unblinded. To unblind 
the patient, call the MCCC Registration Office (507-284-2753) Monday through Friday, 
8:00 a.m. to 4:30 p.m. Central Time to find out if the patient was receiving nasal rose 
geranium in sesame oil or nasal isotonic saline. Upon confirmation by the nurse/research 
staff call that all questionnaires have been completed and sent in the mail, the treatment 
assignment may be unblinded. Patients who were assigned nasal isotonic saline may 
proceed with the crossover phase and must be re-registered per the instructions in Section 
6.9b. 
 
 

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8.0 
Dosage Modification Based on Adverse Events  
If the patient develops any Grade 2 or higher Adverse Event (AE) attributed to rose geranium in 
sesame oil nasal spray or isotonic nasal saline, it should be recorded on the AE Form and the 
study spray should be reduced to once a day or be stopped per clinician discretion. The patient 
should continue to be followed according to protocol criteria.  
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care: 
Other treatment as necessary for control of chemotherapy related symptoms is allowed, with the 
exception of utilization of other topical nasal therapies.  
10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
 
All sites 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic_a
pplications/docs/PregnancyReportFormUpdated.pdf 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
http://livecycle2.mayo.edu/worksp
ace/?startEndpoint=MC4158-
56/Processes/MC4158-56-
Process.MC4158-56 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo
.edu and 
RSTP2CSAES@mayo.edu 
Non Mayo sites – complete and 
forward to 
RSTP2CSAES@mayo.edu 

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Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
http://livecycle2.mayo.edu/workspace/?startEndpoint=
MC4158-56/Processes/MC4158-56-Process.MC4158-
56 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo
.edu and 
RSTP2CSAES@mayo.edu 
 
 
 
Non-Mayo 
Clinic Sites 
MedWatch 3500A:  
http://www.fda.gov/downloads/AboutFDA/ReportsManu
alsForms/Forms/UCM048334.pdf 
RSTP2CSAES@mayo.edu and 
MCCCCRO@mayo.edu 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0 A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  

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Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 

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● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer. 
10.4 
Expedited Reporting Requirements for Commercial or Commercial Imaging Agents 
(Non-IND) Agent(s) ONLY:  
10.41 Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND trial within 30 Days of the Last Administration of a Commercial 
Agent1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥24 hrs 
7 Calendar Days 
24-Hour  
3 Calendar 
Days 
Not resulting in 
Hospitalization  
≥24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 

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10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56 for investigational agents or 
commercial/investigational agents on the same arm.  Will automatically be sent 
to CANCERCROSAFETYIN@mayo.edu and RSTP2CSAES@mayo.edu 
Non-MCCC Institutions: 
Use form MedWatch 3500A 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
Submit copies to MCCCCRO@mayo.edu, RSTP2CSAES@mayo.edu and  
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that  
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 

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Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56, to submit to 
CANCERCROSAFETYIN@mayo.edu. The Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
Non-MCCC Institutions:  
Submit to your IRB as required by your institutional policies. 
Submit copies to FDA, RSTP2CSAES@mayo.edu and  
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as 
Grade 5 “General disorders and administration site 
conditions-Disease progression”under the system organ 
class (SOC) of the same name. Evidence that the death was 
a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be 
submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 

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• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 

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Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions other than nasal symptoms do not need to be graded.  
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
11.0 
Treatment Evaluation/Measurement of Effect  
Effect of nasal preparation will be measured by differences in reported nasal symptoms 
before and after, utilizing responses to questionnaires in Appendix 1 and 2.  
12.0 
Descriptive Factors  
12.1 
Prior different treatments tried for nose symptoms: 0 vs 1 vs 2 vs 3+ 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. If 
the patient received treatment, the patient may continue treatment at the discretion of the 

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physician as long as there are not safety concerns. The patient will continue in the Active 
Monitoring/Treatment phase of the study, as per section 4.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted.  
13.2 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. If the patient received treatment, the patient may continue treatment at 
the discretion of the physician as long as there are not safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, as per section 4.0 of the 
protocol. 
13.3 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
14.0 
Body Fluid Biospecimens: None 
15.0 
Drug Information 
15.1 
Rose Geranium Extract (genus Pelargonium) in Sesame Oil Nasal Spray 
 
 
15.11 Background: Rose geranium in sesame oil nasal spray is a compounded product 
utilizing essential rose geranium oil and sesame oil. 
 
15.12 Formulation: We will obtain Rose Geranium from Professional Compounding 
Centers of America (PCCA). 
 
0.2 mL of Rose Geranium oil will be mixed with 119.8 mL of Sesame Oil.  After 
mixing the compounded product will be aliquoted into  nasal spray bottles (30 
mL / bottle).  The study agent will be compounded by Gateway Pharmacy 
(Bismarck, ND). 
 
The lot number of all components used per batch of agent will be recorded on a  
Formula Worksheet (Each batch will be assigned a unique log number on the day 
the compound is mixed. 
 
The nasal spray containers with screw cap closure will be purchased from 
Professional Compounding Centers of America (PCCA). The contents of each 
container will be 30 ml. 
 
Each spray will deliver about 0.1ml of drug to the patient. 
 
15.13 Preparation and storage: The rose geranium in sesame oil should be stored 
in its original closed container at room temperature 20°C to 25°C (68°F to 
77°F). Excursions are permitted between 15°C to 30°C (59°F to 86°F) and 
protected from light. 
15.14 Administration:  Instill 1 spray into each nostril twice daily.  One additional 
spray can be administered if the first spray is not a full spray.  
 
 
15.15 Pharmacokinetic information: None available.  

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15.16 Potential Drug Interactions: None   
 
15.17 Known potential toxicities: Lipoid pneumonia (rare). 
 
15.18 Study agent procurement:   
Gateway Pharmacy (Bismarck, ND) will supply Rose Geranium Oil Nasal Spray 
to the registered sites participating on the trial. 
 
Mayo and each participating MNCCTN site will order a starter supply of blinded 
Rose Geranium in Sesame Oil Nasal Spray/Placebo and open label supply from 
Gateway Pharmacy.  Fax the Drug Order Form to: 
 
Gateway Pharmacy 
 
Bismarck, ND 
 
FAX: 701-258-6391 
 
Phone: 701-354-7591 
 
Registration Office personnel will monitor the supply of blinded Rose Geranium 
in Sesame Oil Nasal Spray/Placebo at each participating site and will coordinate 
with Gateway Pharmacy to send additional supplies to sites as needed. 
 
Outdated or remaining drug/product should be destroyed on site.   
 
 
15.19 Nursing Guidelines:  
1. Warn patients to avoid contact with the eyes as this can cause eye irritation. 
2. When applied nasally, patients may experience a bad taste 
3. Instruct patients to report any rash or burning with application 
4. Agent should be stored at room temperature 
15.2 
Placebo 
A matching isotonic nasal saline spray will be identical in appearance to the Rose 
Geranium Oil Nasal Spray.  The isotonic nasal saline spray will contain 0.9% 
Sodium Chloride. It will also contain 0.133% of benzalkonium chloride solution 
50% per 100ml of normal saline, as a preservative. The nasal spray containers with 
screw cap closure will be purchased from Professional Compounding Centers of 
America (PCCA). The contents of each container will be 30 ml. The placebo spray 
should be stored at controlled room temperature (20°-25 ° C or 68°-77° F), with 
excursions to 15-30°C (59-86°F) permitted.  
 
15.21 Optional crossover phase:  Patients initially enrolled on the placebo arm have 
the option to crossover and receive 2 weeks of the Rose Geranium Oil Nasal 
Spray.   
16.0 
Statistical Considerations and Methodology  
16.1 
Study Design 
This is a randomized, double-blinded, controlled study to determine the ability of rose geranium 
in sesame oil nasal spray to alleviate nasal vestibulitis in patients undergoing systemic, 
antineoplastic therapy when compared with isotonic nasal saline.  Patients will be randomized in 
a 1:1 ratio to receive either rose geranium in sesame oil nasal spray or isotonic nasal saline.  
Randomization will be stratified on the basis of sex (female; male), age in years (≤50; > 50), and 
seasonal allergies and/or asthma (yes; no).    To enhance participation, patients who were 

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assigned isotonic nasal saline have the option to receive rose geranium in sesame oil nasal spray 
within two weeks after completion of isotonic nasal saline (i.e. provided that they are still 
receiving chemotherapy at the time of “crossover”) and continue to receive rose geranium in 
sesame oil nasal spray for two weeks. 
16.2 
Description of Randomization Routine   
After a patient is registered they will be assigned to one of the two arms (rose geranium in sesame 
oil nasal spray; isotonic nasal saline) in a 1:1 ratio utilizing a dynamic allocation algorithm based 
on the methods by Pocock and Simon (10). The goal of the algorithm is to maintain arm balance 
with respect to the aforementioned stratification factors.  In order to ensure that arm assignment is 
not deterministic, a level of randomness has been added to the algorithm such that patients will be 
assigned to the arm that leads to more imbalance 10% of the time.  Dynamic allocation is a common 
approach in cancer clinical trials where we desire arms to be balanced across several prognostic 
factors.  The method is considered robust because it ensures excellent  
arm balance overall and 
within the stratification factor levels, even with a large number of stratification factors (11).  
16.3 
Sample Size, Accrual Time, and Study Duration 
Based on our clinical experience, we assume that 30% of the patients on the isotonic nasal saline 
arm will report that the nasal symptom that was most prominent prior to starting the study will be 
moderately better or very much better 2 weeks after initiation of the nasal spray.  We hypothesize 
that 65% of the patients receiving rose geranium in sesame oil nasal spray will indicate that their 
most prominent nasal symptom prior to starting the study will be moderately better or very much 
better 2 weeks after initiation of the nasal spray.  This corresponds to an odds ratio of 1 under the 
null hypothesis and an odds ratio of 4.33 (rose geranium in sesame oil nasal spray / isotonic nasal 
saline).  Using a Fisher’s exact test and testing at a 0.05 two-sided significance level, we will 
have 85% power to detect this difference if we randomize 80 eligible and evaluable patients on 
the study.  We anticipate that up to 20% of patients will not have met the eligibility criteria and/or 
not be evaluable for response assessment, and thus the target sample size will be inflated to 106 
patients (53 per arm).   
 
Using conservative estimates, we anticipate an accrual rate of 10 patients per month; therefore, to 
achieve the targeted accrual of 50 patients per arm, we anticipate that the accrual period will be 
approximately 10 months.  Because the patients randomized to receive isotonic nasal saline may 
elect to receive rose geranium in sesame oil nasal spray for 2 weeks following the 2-week active 
monitoring phase, the corresponding total study duration will be approximately 11 months. 
May, 2022 addendum:  This month it became apparent that 6 patients erroneously received the 
opposite product to which they had been randomized to receive.  This was due to a pharmacy 
error, by the institution that makes the rose geranium in sesame oil and the nasal saline 
containers.  When this pharmacy had prepared a batch of product and sent such to one 
participating institution, they put nasal saline code numbers on 5 containers of rose geranium in 
sesame oil and rose geranium in sesame oil code numbers on 5 containers that had nasal saline 
product.  Only 6 of these containers were given to patients. Given this, we plan to increase the 
accrual number by 6 patients, to a total of 106 patients. The 6 patients that received the wrong 
treatment will be retained on the study and included in an intent-to-treat analyses (analyzing 
patients according to the arm in which they were randomized). As sensitivity analyses, we will 
also perform a per-protocol analysis (analyzing patients according to the treatment they received) 
and a separate analysis after excluding the 6 patients that received the wrong treatment.  The 
additional 6 accrued patients will assure that there is adequate power for each of these sensitivity 
analyses. 

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16.4 
Statement for Primary Endpoint 
 
16.4.1 Primary Endpoint 
The primary endpoint is a binary variable indicating whether the patient achieves a 
response (yes; no) at 2 weeks after initiating the nasal spray.   Response is determined 
from a patient global impression of change scale and is defined as a patient reporting that 
the nasal symptom that was most prominent prior to starting the study has been 
moderately better or very much better 2 weeks after initiating the nasal spray.  
 
 
16.4.2 Analysis Plan for Primary Endpoint 
The primary analysis will be based on a modified intention-to-treat (mITT) population, 
defined as all patients who signed a consent form, met the eligibility criteria, indicated 
their most bothersome nasal symptom at baseline, completed the patient global 
impression of change scale 2 weeks after initiating the nasal spray, and were randomized; 
furthermore, these patients will be analyzed in the arms to which they were randomized. 
 
The number and percentage of patients experiencing a response 2 weeks after initiating 
the nasal spray will be estimated within each randomized arm and the corresponding two-
sided 95% exact (Clopper-Pearson) confidence interval provided.  A between-arm 
comparison of the proportion of patients experiencing a response 2 weeks after initiating 
the nasal spray will be made using the Fisher’s exact test.  Statistical significance will be 
assessed at the 5% level.  In addition, the estimated odds ratio with the 95% confidence 
interval that matches the Fisher’s exact test will be provided. 
 
16.4.3 Planned Sensitivity Analyses for Primary Endpoint 
To assess the robustness of the primary results, a supportive analysis is planned.  A 
logistic regression analysis will be undertaken to estimate the treatment effect after 
adjusting for the three stratification factors, the corresponding baseline severity for the 
most prominent nasal symptom, and potential confounding variables. Additionally, the 
primary analysis will be repeated to include patients who did not complete the patient 
global impression of change scale 2 weeks after initiating the nasal spray but would 
otherwise be included in the mITT population.  For this analysis, we will assume that the 
missing values for these patients represent no improvement.  
16.5 
Analysis Plan for Secondary Endpoints 
For the most prominent nasal symptom indicated at baseline, patients will record the 
severity on an ordinal scale of 1=mild, 2=moderate, 3=severe, and 4=very severe.  Two 
weeks after initiating the nasal spray the patients will record the severity of the most 
prominent nasal symptom as 0=none, 1=mild, 2=moderate, 3=severe, and 4=very severe.   
A shift table will be created to descriptively display the number of patients who record a 
1, 2, 3, or 4 at baseline and the shift two-weeks after initiating the nasal spray. 12[In 
addition, the within-patient change in severity of the most prominent nasal symptom will 
be calculated 2 weeks after initiating the nasal spray and summarized descriptively within 
each arm.  The Wilcoxon rank-sum test will be performed, and the methods of Hodges 
and Lehmann will be applied to compute a point estimate and confidence interval for the 
difference in medians between the two arms.  As a supportive analysis, the van Elteren 
statistic, which is an extension to the Wilcoxon rank-sum test that accounts for the 
stratification factors, will be calculated.  Furthermore, we will model the ordinal response 
data obtained two weeks after initiating the nasal spray with a proportional odds 

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cumulative logit model; explanatory variables will include arm, corresponding baseline 
severity for the most prominent nasal symptom, the stratification factors, and other 
potential confounding variables.   
In addition to summarizing the most prominent nasal symptom that the patient indicated 
at baseline, each nasal symptom (dryness, pain, bleeding, and scabbing) will be 
descriptively summarized, tabulated, and plotted according to arm at baseline, and at 1 
and 2 weeks post-baseline; additionally, we will group patients according to baseline 
severity for each symptom and summarize changes over time and according to arm.  Shift 
tables will also be generated to descriptively display the number of patients who record a 
1, 2, 3, or 4 at baseline and the shift one- and two-weeks after initiating the nasal spray.  
These analyses are descriptive in nature and are intended to further contextualize the 
main study findings that are based on analyzing the most prominent nasal symptom 
reported by the patient. 
The constellation of adverse events (AEs) as scored using the National Cancer Institute 
Common Terminology Criteria for Adverse Events, v5.0 (CTCAE v5.0) will be 
summarized within arms by reporting the number and percentage of patients.  
Specifically, to evaluate the AE profiles  associated with each arm, the maximum grade 
for each type of AE will be recorded for each patient and frequency tables will be 
reviewed to determine overall patterns and compared between arms using Wilcoxon tests.  
16.6 
Analysis Plan for Crossover Phase 
The crossover option for patients assigned to receive isotonic nasal saline is intended to 
provide access to a potentially beneficial treatment for nasal vestibulitis.  The number and 
proportion of patients who elect to experience therapy with the rose geranium in sesame 
seed oil will be reported.  Data from this portion of the protocol will be descriptively 
summarized with no planned statistical comparisons.  
16.7 
Missing Data 
Every attempt will be made to obtain complete data for each patient.  For the primary 
endpoint, evaluable patients are defined as patients who indicated their most bothersome 
nasal symptom at baseline and completed the patient global impression of change scale 2 
weeks after initiating the nasal spray.  We are targeting 106 patients to obtain 80 eligible 
and evaluable patients for the primary endpoint.   For all other analyses, no missing data 
will be imputed; all available data will be listed and summarized.    
16.8  
Study Monitoring 
16.8.1 Data and Safety Monitoring Board 
This study will be monitored by the Mayo Clinic Cancer Center Data Safety and 
Monitoring Board (DSMB) twice per year. The DSMB will review administrative 
information, accrual, adverse events, and interim analysis results.  Early termination of 
accrual will be considered if there is evidence of unacceptable toxicity. 
16.8.2 Adverse Event Stopping Rule 
Throughout the course of the study, we will monitor AEs in both study arms, and may 
suspend accrual if patients are experiencing a large number of AEs.  Accrual will be 
temporarily suspended to this study if at any time we observe 5 or more of the first 20 
patients experiencing any grade 3+ AEs that the study team considers to be at least possibly 
related to rose geranium (i.e. an AE with attribute specified as “possible”, “probable”, or 

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“definite”) and also, the incidence of these grade 3+ AEs must be higher in the rose 
geranium arm. 
After the first 20 patients, if more than 25% of the patients have grade 3+ AEs that the 
study team considers to be at least possibly related to rose geranium (i.e. an AE with 
attribute specified as “possible”, “probable”, or “definite”) and the incidence of these grade 
3+ AEs is higher in the rose geranium arm, then accrual will be temporarily suspended.    
The AE stopping rule may be modified if during the course of the study, new information 
becomes available which suggests that such a modification is necessary, or if, after 
temporarily stopping accrual, the above rule is found to be overly conservative. If accrual 
is temporarily suspended, the study AEs will be reviewed by the investigators and the Mayo 
Clinic DSMB.  Based on this review, accrual will then be either restarted or permanently 
stopped. 
16.8.3 Accrual Monitoring Stopping Rule 
Patient accrual will be closely monitored by the investigators and study statistician on a bi-
weekly basis. If the accrual rate falls below 50% of expected accrual rate, investigators will 
carefully review feedback from sites and consider taking measures to encourage patient 
enrollment. 
16.9 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of gender, race, or ethnic 
origin. 
There is no information currently available regarding differential effects of this regimen in 
subsets defined by gender, race, or ethnicity, and there is no reason to expect such 
differences to exist. Therefore, although the planned analyses will look for differences in 
treatment effect based on gender, racial, and ethnic groupings, the sample size is not 
increased in order to provide additional power for subset analyses.   
 
 
 

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Expected sizes of race by ethnicity and gender subsets for patients participating in this study 
 
are shown in the table below. 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
4 
0 
0 
0 
4 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
5 
0 
0 
0 
5 
White 
55 
38 
4 
0 
97 
More Than One Race 
0 
0 
0 
0 
0 
Total 
64 
38 
4 
0 
106 
 
Ethnic  
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
 
 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of 
the original peoples of North, Central, or South America, and who maintains 
tribal affiliations or community attachment. 
 
Asian – a person having origins in any of the original peoples of the Far 
East, Southeast Asia, or the Indian subcontinent including, for example, 
Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine 
Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine 
Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
 
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
 
Native Hawaiian or other Pacific Islander – a person having origins in 
any of the original peoples of Hawaii, Guam, Samoa, or other Pacific 
Islands. 
 
White – a person having origins in any of the original peoples of Europe, 
the Middle East, or North Africa. 
 
 
 

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17.0  
Pathology Considerations/Tissue Biospecimens: None 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up: none 
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Labeling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.6 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.0  
Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded: Rose Geranium in Sesame Oil Nasal Spray and Isotonic 
Nasal Saline will be provided free of charge. 
19.3 
Other budget concerns: 
The Breast Cancer Research Foundation (BCRF) has provided Mayo Clinic with funding 
to support the costs of running this study. 
 
 
 

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20.0 
References 
1. 
Ruiz JN, Belum VR, Boers-Doets CB, Kamboj M, Babady NE, Tang YW, et al. Nasal vestibulitis 
due to targeted therapies in cancer patients. Support Care Cancer. 2015;23(8):2391-8. 
2. 
Reh DD, Hur K, Merlo CA. Efficacy of a topical sesame/rose geranium oil compound in patients 
with hereditary hemorrhagic telangiectasia associated epistaxis. Laryngoscope. 2013;123(4):820-2. 
3. 
Bjork-Eriksson T, Gunnarsson M, Holmstrom M, Nordqvist A, Petruson B. Fewer problems with 
dry nasal mucous membranes following local use of sesame oil. Rhinology. 2000;38(4):200-3. 
4. 
Johnsen J, Bratt BM, Michel-Barron O, Glennow C, Petruson B. Pure sesame oil vs isotonic 
sodium chloride solution as treatment for dry nasal mucosa. Arch Otolaryngol Head Neck Surg. 
2001;127(11):1353-6. 
5. 
Kim JY, Jung JW, Choi JC, Shin JW, Park IW, Choi BW. Recurrent lipoid pneumonia associated 
with oil pulling [Correspondence]. Int J Tuberc Lung Dis. 2014;18(2):251-2. 
6. 
Kuroyama M, Kagawa H, Kitada S, Maekura R, Mori M, Hirano H. Exogenous lipoid pneumonia 
caused by repeated sesame oil pulling: a report of two cases. BMC Pulm Med. 2015;15:135. 
7. 
King D, Mitchell B, Williams CP, Spurling GK. Saline nasal irrigation for acute upper respiratory 
tract infections. Cochrane Database Syst Rev. 2015(4):CD006821. 
8. 
Adappa ND, Wei CC, Palmer JN. Nasal irrigation with or without drugs: the evidence. Curr Opin 
Otolaryngol Head Neck Surg. 2012;20(1):53-7. 
9. 
Chong LY, Head K, Hopkins C, Philpott C, Glew S, Scadding G, et al. Saline irrigation for 
chronic rhinosinusitis. Cochrane Database Syst Rev. 2016;4:CD011995. 
10. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics. 1975;31(1):103-15. 
11. 
Therneau TM. How many stratification factors are "too many" to use in a randomization plan? 
Control Clin Trials. 1993;14(2):98-108. 
12.  
Dmitrienko A and Koch GG.Analysis of Clinical Trials Using SAS: A Practical Guide, Second 
Edition.  2017. 
 
 

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Appendix I.  Baseline Pre-nasal Spray Questionnaire 
 
 
1. How much of a problem has nose DRYNESS been, ON AVERAGE, over the past two days? 
(check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
2. How much of a problem has nose PAIN or TENDERNESS been, ON AVERAGE, over the past 
two days? (check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
3. How much of a problem has nose BLEEDING been, ON AVERAGE, over the past two days? 
(check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
4. How much of a problem has nose SCABBING been, ON AVERAGE, over the past two days? 
(check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
5. How much of a problem has nose SORES been, ON AVERAGE, over the past two days? (check 
one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
6. Have you had nose symptoms, other than dryness, pain, bleeding,  scabbing, or  nose sores over 
the past two days? (check one) 
___ No 
___ Yes 
  
(If yes), Please describe: _________________________________________________ 
 

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7. Which symptom is the most bothersome to you, which you would like treatment for? (check one) 
__ Dryness 
__ Discomfort 
__ Bleeding 
__ Scabbing 
__ Sores 
  
8. Have you been taking any medications or using any topical remedies for nose symptoms? (check 
one) 
___ No 
___ Yes  
(If yes), 
Please describe the name of the medication: ___________________________________ 
 
9. Do you take any aspirin or blood thinners? (check one) 
___ No  
___ Yes 
(If yes), Which medication do you take? _____________________________________ 
 
 
10. Do you have a history of asthma? (check one) 
 
___ No  
___ Yes  
 
 
11. Do you have a history of allergies (NOT including allergies or sensitivities to medications)? (check 
one) 
 
___ No  
___ Yes 
(If yes), please list any current medications you take for this? 
____________________________________________________________________ 
 
 
12. Do you currently smoke? (check one) 
 
___ No  
___ Yes 
 
(If no), Have you ever smoked? (check one) 
 
___ No  
___ Yes 
(If yes), what year did you quit?  (yyyy) __ __ __ __  
 
 
 
 

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Appendix II. Nasal Symptom and Patient Experience Questionnaire 
 
Most prominent nasal symptom reported at baseline:  
(Nurse/research staff will complete everything above this line) 
 
1. How much of a problem has nose DRYNESS been, ON AVERAGE, over the past two days? 
(check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
2. How much of a problem has nose PAIN or TENDERNESS been, ON AVERAGE, over the past 
two days? (check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
3. How much of a problem has nose BLEEDING been, ON AVERAGE, over the past two days? 
(check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
4. How much of a problem has nose SCABBING been, ON AVERAGE, over the past two days? 
(check one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
5. How much of a problem has nose SORES been, ON AVERAGE, over the past two days? (check 
one) 
__ None 
__ Mild 
__ Moderate 
__ Severe 
__ Very Severe 
 
  
6. Have you had nose symptoms, other than dryness, pain, bleeding, scabbing or nose sores, over the 
past two days? (check one) 

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___ No 
___ Yes 
  
(If yes), please describe: _____________________________________________  
 
 
7. Since starting this study, the nasal symptom that was most prominent in the beginning (listed 
above Question 1)  has been: ( please circle one response) 
 
-3 
        -2     
-1 
           0 
   +1 
 
+2 
 
+3 
 
 
 
 
 
8. How helpful is the nose spray in relieving your nose symptoms? (please circle one response) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
9. Since starting this study, I think that I was on: (please check one response) 
 
 Nasal symptom relieving nasal spray 
 Placebo nasal spray 
 
10. Over the past week, the spray was prescribed to be used 14 times (twice each day).  How many 
times do you estimate that you actually used it over the last week? (please check one) 
 
 12-14 times 
 10-12 times 
 6-11 times 
 0-5 times 
 
11. Please provide any comment on your use of the study spray, if indicated 
______________________________________________________ 
______________________________________________________ 
 
12. Do you have any unpleasant effects from the nose spray? (check one) 
 
 
No 
Yes 
(If yes), please describe: _____________________________________ 
 
 
 
 
Very 
much 
worse 
Very much 
better 
About 
the 
same 
A little 
better 
Moderately 
better 
Moderately 
worse 
A little 
worse 
Not at all 
helpful 
Completely 
resolves my 
nasal 
symptoms 

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Appendix III PATIENT INFORMATION SHEETS 
Patient Completed Booklet 
BASELINE 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains multiple questions 
about your ‘quality of life’ as a patient receiving nasal spray. 
 
Please answer all of the questions, even if they sound similar to a question you have already 
answered.   
 
 
1. This booklet contains the following questionnaires that are to be completed prior to treatment 
(baseline): 
a. Baseline Pre-nasal Spray Questionnaire 
 
2. You can call anytime with any concerns or questions. 
 
3. It is very important that you return the booklet to us, whether you finish the study or not. 
 
 
Reminder: If you start any other nasal spray while on this study, notify your nurse/research staff. 
 
 
 
Thank you for taking the time to help us. 
 
 
 
 

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Patient Completed Booklet 
TREATMENT 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains multiple questions 
about your ‘quality of life’ as a patient receiving nasal spray. 
 
Please answer all of the questions, even if they sound similar to a question you have already 
answered.   
 
 
1. This booklet contains the following questionnaires that are to be completed during treatment: 
a. Nasal Symptom and Patient Experience Questionnaire 
 
2. You can call anytime with any concerns or questions. 
 
3. It is very important that you return the booklet to us, whether you finish the study or not. 
 
 
Reminder: If you start any other nasal spray while on this study, notify your nurse/research staff. 
 
Thank you for taking the time to help us.