Study to Assess the Safety and Effect of Repeated Administration of Granulocyte Colony-Stimulating Factor (G-CSF; Filgrastim) on Hot Flashes and Other Vasomotor Symptoms of Menopause in Postmenopausal Women
Phase: PHASE1
Conditions: Postmenopausal Symptoms
Sponsor: MenoGeniX, Inc.



Protocol MNGX-102 
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TABLE OF CONTENTS 
 
1 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .......... 14 
2 
INTRODUCTION ................................................................................................... 15 
2.1 
Background Therapeutic Information ................................................................. 15 
2.2 
Background and Significance ............................................................................. 16 
2.3 
G-CSF ................................................................................................................. 17 
2.4 
Safety Experience with G-CSF ........................................................................... 19 
2.4.1 Previous G-CSF Experience in Phase 1 Single-Dose Healthy Volunteer Studies
 20 
2.4.2 Previous G-CSF Experience in Chemotherapy-induced, Congenital and 
Idiopathic Severe Neutropenia ...................................................................... 22 
2.5 
Background and Rationale for the Current Study ............................................... 23 
2.5.1 Clinical Study MNGX-101: A Randomized, Double-Blind, Placebo-Controlled 
Pilot Phase 1b Study to Assess the Safety and Effect of a Single Subcutaneous 
Dose of Granulocyte Colony-Stimulating Factor (G-CSF; filgrastim) to Treat 
Hot Flashes in Postmenopausal Women ....................................................... 23 
2.5.2 Original Case Study ...................................................................................... 28 
2.5.3 G-CSF Compared to Hormone Therapy and Paroxetine .............................. 29 
2.5.4 Dose Selection ............................................................................................... 33 
3 
STUDY OBJECTIVES ........................................................................................... 34 
4 
STUDY DESIGN AND PLAN ............................................................................... 35 
4.1 
Treatment Plan and Regimen .............................................................................. 35 
4.1.1 Treatment Plan .............................................................................................. 35 
4.1.2 Dose, Time of Administration and Duration of Treatment ........................... 35 
4.2 
End of Study ........................................................................................................ 35 
4.3 
NIH-assigned Data Safety Reviewer Board ........................................................ 35 
5 
SUBJECT POPULATION ..................................................................................... 36 
5.1 
Inclusion Criteria ................................................................................................. 36 
5.2 
Exclusion Criteria................................................................................................ 36 
6 
STUDY DRUG(S) AND CONCOMITANT MEDICATIONS ........................... 39 
6.1 
Description and Handling of Study Drug............................................................ 39 
6.1.1 Study Drug .................................................................................................... 39 

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6.1.2 Packaging and Labeling ................................................................................ 39 
6.1.3 Storage and Handling .................................................................................... 39 
6.1.4 Procedure....................................................................................................... 39 
6.1.5 Breaking the Blind ........................................................................................ 40 
6.2 
Preparation and Administration of Study Drug .................................................. 40 
6.2.1 Adverse Events Associated with Drug Administration ................................ 40 
6.3 
Drug Accountability ............................................................................................ 41 
6.4 
Concomitant Medications/Dietary Supplements................................................. 41 
6.4.1 Prohibited Concomitant Medications and Potential for Drug Interactions ... 41 
7 
STUDY PROCEDURES ......................................................................................... 42 
7.1 
Subject Enrollment and Study Drug Randomization .......................................... 42 
7.2 
Study Procedures and Assessments .................................................................... 42 
7.2.1 Clinical Laboratory Tests .............................................................................. 48 
7.2.2 Daily Hot Flash Diary ................................................................................... 49 
7.2.3 Questionnaires ............................................................................................... 50 
7.2.4 Coordinator-to-Subject Phone Calls ............................................................. 50 
7.2.5 Final Coordinator-to-Subject Phone Call ...................................................... 50 
7.3 
Criteria for Study Discontinuation ...................................................................... 50 
8 
ADVERSE EVENTS ............................................................................................... 51 
8.1 
Safety Assessment ............................................................................................... 51 
8.1.1 Clinical Laboratory Abnormalities ............................................................... 51 
8.2 
Definition of Adverse Event ............................................................................... 51 
8.3 
Definition of Serious Adverse Event .................................................................. 51 
8.4 
Adverse Event Reporting Period ......................................................................... 52 
8.5 
Adverse Event Assessment and Documentation ................................................. 52 
8.5.1 Definition of Severity of Adverse Events to Study Drug ............................. 53 
8.6 
Serious Adverse Event Reporting Requirements ................................................ 54 
8.7 
Serious Adverse Event Report Distribution ........................................................ 54 
8.8 
Expected Adverse Events .................................................................................... 55 
8.9 
Pregnancy ............................................................................................................ 55 
9 
STATISTICAL METHODS .................................................................................. 56 

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9.1 
Sample Size ......................................................................................................... 56 
9.2 
Study Endpoints .................................................................................................. 56 
9.2.1 Safety............................................................................................................. 56 
9.2.2 Evaluation of Effect ...................................................................................... 56 
9.2.3 Exploratory Analyses .................................................................................... 57 
9.3 
Data Analysis ...................................................................................................... 57 
9.3.1 Evaluation of Effect ...................................................................................... 57 
9.3.2 Exploratory Analysis ..................................................................................... 58 
9.3.3 Safety ............................................................................................................. 58 
10 STUDY CONDUCT ................................................................................................ 60 
10.1 Adherence to the Protocol ................................................................................... 60 
10.2 Recording and Collecting of Data ....................................................................... 60 
10.2.1 Case Report Forms ........................................................................................ 60 
10.2.2 Study Files and Subject Source Documents.................................................. 60 
10.3 Monitoring .......................................................................................................... 61 
10.3.1 Drug Accountability ...................................................................................... 61 
10.4 Retention of Records ........................................................................................... 61 
10.5 Inspection ............................................................................................................ 62 
10.6 Legal and Ethical Requirements ......................................................................... 62 
10.6.1 Good Clinical Practice .................................................................................. 62 
10.6.2 Institutional Review Board Approval ........................................................... 62 
10.6.3 Informed Consent .......................................................................................... 63 
10.6.4 Study Termination ......................................................................................... 63 
10.6.5 Regulatory Approval ..................................................................................... 63 
10.7 Compensation, Insurance, and Indemnity ........................................................... 63 
10.8 Disclosure of Information ................................................................................... 64 
10.9 Confidentiality and Data Protection .................................................................... 64 
10.10 Study Report and Publications ............................................................................ 65 
11 REFERENCES ........................................................................................................ 66 
12 APPENDICES ......................................................................................................... 69 
Appendix 1: 
Study Procedures Table ........................................................................ 70 

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Appendix 2: 
Prohibited Drugs and Supplements ....................................................... 72 
Appendix 3: 
Hot Flash Related Daily Interference Scale .......................................... 74 
Appendix 4: 
Insomnia Severity Index ....................................................................... 75 
Appendix 5: 
Menopause Specific Quality of Life Questionnaire .............................. 76 
Appendix 6: 
Fatigue Severity Scale ........................................................................... 77 
Appendix 7: 
Arthritis Impact Measurement Scale .................................................... 78 
 
 
 
 
 
 

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SPONSOR SIGNATURES 
 
Protocol MNGX-102 
 
A Randomized, Double-Blind, Placebo-Controlled Phase 1b Study to Assess the Safety and Effect of 
Repeated Administration of Granulocyte Colony-Stimulating Factor (G-CSF; filgrastim) on Hot 
Flashes and Other Vasomotor Symptoms of Menopause in Postmenopausal Women 
Final, Version 4, Amendment 3 
12 October 2020 
PROTOCOL AUTHORS: 
 
 
Signature:  
 
 
Date 
 
 
 
Signature:  
 
  
 
 
PROTOCOL APPROVED BY: 
 
 
Signature:  
 
 
 
Date 
 
 
 
 

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MENOGENIX, INC.  
Bioscience Park Center  
12635 East Montview Boulevard 
Suite 100 
Aurora, CO 80045 
 
STUDY ACKNOWLEDGMENT 
 
A Randomized, Double-Blind, Placebo-Controlled Phase 1b Study to Assess the Safety and Effect of 
Repeated Administration of Granulocyte Colony-Stimulating Factor (G-CSF; filgrastim) on Hot 
Flashes and Other Vasomotor Symptoms of Menopause in Postmenopausal Women 
Protocol MNGX-102 
Version 4, Amendment 3 
12 October 2020 
This protocol has been approved by MenoGeniX, Inc. 
 
 
INVESTIGATOR STATEMENT 
 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study in 
compliance with all applicable regulations and guidelines as stated in the protocol and other 
information supplied to me. I will make a reasonable effort to complete the study within the 
time designated. 
 
I will provide all study personnel under my supervision with copies of the protocol and 
access to all information provided by MenoGeniX, Inc. I will discuss this material with them 
to ensure that they are fully informed about the drug(s) and the study. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
 
Print Name 
 
Site Number 
 
 

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PROTOCOL SYNOPSIS 
MenoGeniX, Inc. 
Protocol MNGX-102 
 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled Phase 1b Study to 
Assess the Safety and Effect of Repeated Administration of 
Granulocyte Colony-Stimulating Factor (G-CSF; filgrastim) on Hot 
Flashes and Other Vasomotor Symptoms of Menopause in 
Postmenopausal Women. 
Objectives: 
The primary objective of this Phase 1b study is to assess the safety and 
pharmacodynamic (PD) effect of repeated subcutaneous injection of G-
CSF in healthy postmenopausal women.  
The secondary objective of this proposed study is to assess the efficacy 
of repeated administration of G-CSF in reducing the frequency and 
severity of hot flashes in postmenopausal women.  
The tertiary objectives are to assess additional measures of hot flash 
burden and to test the association between G-CSF administration, 
changes in hot flash frequency and severity, and markers of 
inflammation and reproductive hormones. 
Study Design: 
This is a 12-week, multicenter, randomized, double-blind, placebo-
controlled study. Eligible subjects will be stratified by natural or 
surgical menopause and randomized (1:1) to receive 3 single injections, 
28-days apart, of either 300 mcg G-CSF or placebo. 
Study Phase: 
Phase 1b 
Number of Subjects 
Planned: 
A total of 65 subjects will be enrolled in this study.  
Target Population: 
Healthy female subjects aged 49 to 65 who are naturally 
postmenopausal or aged 40 to 65 who are surgically postmenopausal, 
and experiencing at least 7 moderate to severe hot flashes per day on 
average, or at least 49 moderate to severe hot flashes per week. 
Study Duration: 
Subjects will be followed for 12 weeks to evaluate safety, PD, and 
efficacy.  
Main Eligibility 
Criteria: 
To be eligible for the study, the following eligibility criteria must be 
met: 
Inclusion: 
• 
Female, aged 49 to 65 for natural postmenopausal or aged 40 
to 65 for surgical postmenopausal 
• 
Body Mass Index (BMI) 18 to 35 
• 
At least 7 moderate to severe hot flashes per day on average (or 
at least 49 moderate to severe hot flashes per week) 
• 
Naturally postmenopausal or surgically postmenopausal 
women: 
o Naturally postmenopausal is defined as having no 
menstrual periods for at least 12 months prior to study 

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entry; with a biochemical criteria of menopause (FSH 
≥ the reference range for menopause for the local 
laboratory used for screening) 
o Surgically postmenopausal is defined as at least 3 
months after documented bilateral salpingo 
oophorectomy 
• 
Normal pelvic exam within 2 years 
• 
Normal pap smear (if cervix /uterus were present) within 2 
years 
• 
Signed informed consent 
Exclusion: 
• 
Radiation or chemotherapy-induced (including GnRH agonist) 
menopause  
• 
Prior chemotherapy or radiation therapy for cancer 
• 
Prior diagnosis of hematologic malignancy 
• 
Type 1 diabetics or Type 2 diabetics with HbA1c > 7.0% 
• 
Use of hormone replacement therapy or oral contraceptives 
within the past three months  
• 
Use of alternative or complementary medicines or herbs for 
menopausal symptoms within 30 days (refer to Appendix 2) 
• 
Use of any SSRI or SNRI within 30 days 
• 
Use of selective estrogen receptor modulators within 30 days 
• 
Use of gabapentin within 30 days 
• 
Use of clonidine within 30 days 
• 
Use of megestrol acetate (Megace) within 30 days 
• 
Use of, prescription corticosteroids within 30 days (nasal or 
other inhaled corticosteroids and OTC topical corticosteroids 
excepted) 
• 
Current use of lithium therapy (related to possible risk of G-
CSF) 
• 
History (in the past year) or presence of drug or alcohol use 
which, in the opinion of the Investigator, might compromise 
the study or confound the study results 
• 
History of use of any anti-inflammatory biologics  
• 
History of or current splenomegaly (related to possible risk of 
G-CSF) 
• 
History of sickle cell disease (related to possible risk of G-
CSF) 
• 
High risk for medical complications that might affect the 
subject’s ability to complete the trial without a serious co-
morbid event, based on medical history, physical examination 
and laboratory screening evaluation in the opinion of the 
Investigator 
• 
Presence of an acute or chronic condition (such as a 
hematological, rheumatologic auto-immune disease, chronic 
inflammatory disorder, chronic lung disease or osteoporosis) 

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based on history, clinical, or laboratory evaluation, which, in 
the opinion of the Investigator, might compromise the study, 
confound the study results or place the subject at risk  
• 
Follicle stimulating hormone (FSH below the reference range 
for menopause for the local laboratory used for screening 
• 
Thyroid stimulating hormone (TSH) outside normal limits at 
study entry 
• 
Absolute neutrophil count (ANC) ≤ 1.0 x 109/L 
• 
Total white blood cell count (WBC) ≤ 3.0 x 109/L 
• 
Platelet count (PLT) ≤ 150 x 109/L  
• 
Hemoglobin count (HGB) consistent with anemia 
• 
Positive urine pregnancy test at Baseline visit 
• 
Allergy or hypersensitivity to E coli-derived proteins‚ G-CSF‚ 
or any component of the product 
• 
Mentally or legally incapacitated such that informed consent 
cannot be obtained 
• 
Inability or unwillingness to complete daily hot flash diary and 
study questionnaires appropriately 
• 
Participation in another investigational trial within the past 30 
days 
Study Procedures/ 
Frequency: 
Subjects must complete the Screening, plus 14-day run-in period and 
daily diary entry of hot flash frequency and severity, to confirm 
eligibility prior to Baseline. Site staff will call subject on day 15 after 
14-day run-in period to review and record hot flash frequency and 
severity and to confirm eligibility before scheduling the Baseline visit. 
Eligible subjects will be randomized to receive a single injection of G-
CSF or placebo at Baseline and Days 28 and 56. 
Laboratory Assessments: 
• 
Blood samples for clinical chemistry, non-fasting (including 
sodium, potassium, calcium, ALT, AST, bilirubin, creatinine, 
BUN, alkaline phosphatase, and albumin), will be obtained at 
Screening, Baseline and Days 1, 21, 28, 29, 49, 56, 57, and 84. 
If >14 days between Screening and Baseline visit, labs will be 
repeated and reviewed prior to Randomization. 
• 
A blood sample for non-fasting HbA1c will be obtained at 
Screening.  
• 
Blood samples for CBC with differential (including RBC, 
WBC, platelets, hemoglobin, hematocrit, RDW, MCV, MCH, 
MCHC, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, neutrophils [absolute], lymphocytes [absolute], 
monocytes [absolute], eosinophils [absolute], basophils 
[absolute]) will be obtained at Screening, Baseline, Days 1, 21, 
28, 29, 49, 56, 57, and 84. The lab results from the CBC with 
differential obtained at Days 1, 21, 28, 29, 49, 56, 57, and 84 
will not be returned to the Investigator in order to avoid 
treatment unblinding and will be reviewed by the 
Medical/Safety Monitor.  

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• 
Serum samples for circulating hormone levels (including FSH, 
LH, TSH, DHEA, DHEAS, testosterone, and estradiol) will be 
obtained at Baseline and at Days 1, 21, 28, 29, 49, 56, 57, and 
84.  
• 
A blood sample for FSH and TSH will be obtained at Screening 
for verification of inclusion criteria. 
• 
Serum samples for circulating cytokines (including but not 
limited to IL-1, IL-6, IL-8, and TNF-alpha) will be obtained at 
Screening, Baseline, and at Days 1, 21, 28, 29, 49, 56, 57, and 
84.  
Negative urine pregnancy test will be confirmed prior to administration 
of G-CSF or placebo at Baseline and at Days 28 and 56 and also at the 
end of the study (Day 84).  
Study Assessments: Assessments include collection of demographics, 
medical history, smoking and alcohol history, hormone use, 
reproductive and hot flash history, concomitant medications and any 
dietary supplements, and physical exam (including vital signs, 
temperature, weight, and height) completed at Screening. A medical 
history and concomitant medication update will be collected at 
Baseline. Concomitant medications and adverse events will be collected 
at every visit. Vital signs, temperature, and weight also collected at 
Baseline, Days 28, 56 and 84. Collection of daily menopausal 
symptoms using a hot flash frequency and severity diary will be 
completed by subject twice daily (AM and PM) for the duration of 
study.   
Other Assessments/Questionnaires: Questionnaires will include Hot 
Flash Related Daily Interference Scale (HFRDIS), Insomnia Severity 
Index (ISI), Menopause Specific Quality of Life Questionnaire 
(MENQOL), Fatigue Severity Scale (FSS), and Arthritis Impact 
Measurement Scale (AIMS) completed at Baseline and Days 28, 56, 
and 84. 
Coordinator-to-Subject phone calls will occur every week that the 
subjects are not in clinic (calls performed Weeks 1, 2, 5, 6, 9, 10, and 
11) to inquire if any adverse events have occurred, remind subject about 
diary completion, and will be documented.  
Follow-up Coordinator-to-Subject phone call will occur approximately 
28 days following last clinic visit to inquire if any adverse events 
occurred (will be documented), and to inquire about subject status.   
Subjects will be requested to review their hot flash diary at each visit.  
Additional visits and / or tests may be performed if clinically indicated. 
Test Product, Dose, and 
Mode of 
Administration: 
G-CSF will be provided as Neupogen® packaged in individual 1.0 mL 
vials containing 300 mcg filgrastim. Individual vials of sterile 
physiological, preservative free, isotonic saline will be used for placebo.  
Three single subcutaneous injections (repeated 28-days apart), in the 
outer area of either upper arm, of G-CSF (300 mcg)) or placebo (sterile 
physiological saline) in a total volume of 1 mL will be given at Baseline 
visit and Days 28 and 56. 
Safety Evaluation: 
Safety will be assessed by adverse events, clinical laboratory tests 
(clinical chemistry and CBC with differential) and vital signs.  The 

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study will have an independent Data Safety Reviewer assigned by the 
NIH to review safety data at regular intervals. 
Evaluation of Effect: 
Primary Endpoint 
Safety and PD are the primary endpoints of this study.  
Pharmacodynamic Endpoints: Assessment of changes from baseline in 
circulating white blood cells, hormone and inflammatory cytokine 
concentrations. 
 
Secondary Endpoints 
Clinical endpoints 
The effect of 3 repeated doses of G-CSF in the following indicators of 
vasomotor symptoms in women with naturally occurring or surgically 
induced menopause at weeks 2, 4, 6, 8, 10 and 12 weeks post-
administration: 
Hot flashes – change from baseline in: 
• 
Frequency of total daily hot flashes (mild + moderate + severe      
hot flashes)   
• 
Daily frequency of moderate + severe hot flashes 
• 
Daily composite hot flash severity score (1 x mild + 2 x 
moderate + 3 x severe hot flashes)  
• 
Hot flash severity score ((1 x mild + 2 x moderate + 3 x severe 
hot flashes)/total hot flashes) 
Quality of life questionnaires - change from baseline in: 
• 
Hot Flash Related Daily Interference Scale (HFRDIS) 
• 
Insomnia Severity Index (ISI) 
• 
Menopause-specific Quality of Life Questionnaire (MENQOL) 
• 
Fatigue Severity Scale (FSS) 
• 
Arthritis Impact Measurement Scale (AIMS) 
 
Statistical Methods: 
As this is a Phase 1b study intended to evaluate the preliminary safety, 
PD and efficacy of G-CSF in postmenopausal women, no a priori 
assumptions are made regarding estimated treatment effects or statistical 
power. 
Exploratory analyses will be performed to determine the effects of G-
CSF administration on circulating hormone levels (FSH, LH, TSH, 
DHEA, DHEAS, testosterone, and estradiol) and circulating pro-
inflammatory cytokine levels (including but not limited to IL-1, IL-6, 
IL-8, and TNF-alpha). 
Protocol Date: 
12 October 2020 

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GLOSSARY OF ABBREVIATIONS 
AE  
adverse event 
AIMS 
Arthritis Impact Measurement Scale 
ANC 
absolute neutrophil count 
ANOVA  
analysis of variance 
ARDS 
acute respiratory distress syndrome 
ALT  
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BID  
bis in die (twice daily) 
BMI  
body mass index 
BMT 
bone marrow transplant 
BRCA1 
breast or cervical cancer gene 
BRCA2  
breast or cervical cancer gene 
BSA  
body serface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
C 
celsius 
CRA 
Clinical Research Associate 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for 
Adverse Events 
DHEA 
dehydroepiandrosterone 
DHEAS 
dehydroepiandrosterone sulfate 
DSMB 
Data Safety Monitoring Board 
dL  
decilitre 
ECG  
electrocardiogram 
ET  
estrogen 
EPT 
estrogen plus progesterone  
F  
farhrenheit 
FDA 
Food and Drug Administration  
FSH 
follicle stimulating hormone 
FSS 
Fatigue Severity Scale 
g 
 
grams 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte/macrophage colony-
stimulating factor 
GnRH  
gonadotropin-releasing hormone 
HbA1c 
hemoglobin A1c 
HF 
hot flash 
HFRDIS  
Hot Flash Related Daily Interference 
Scale 
HGB 
hemoglobin 
HT 
hormone therapy 
ICF  
informed consent form 
ICH 
International Conference on 
Harmonization 
IL-1 
interleukin 1 
IL-6 
interleukin 6 
IL-8 
interleukin 8 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
IV  
intravenous 
kg 
kilogram 
L 
 
litre 
LH 
lutenizing hormone 
mcg 
microgram 
MCH  
mean corpuscular hemoglobin  
MCHC  
mean corpuscular hemoglobin 
concentration 
MCV  
mean corpuscular volume 
MENQOL 
MENopause specific Quality of Life 
Questionnaire 
mIU 
 
milli international units 
mL 
 
millilitre 
MNGX 
MenoGeniX, Inc. 
NCI  
National Cancer Institute 
OTC 
over-the-counter 
PBPC 
peripheral blood progenitor cell 
PD  
pharmacodynamic 
PI 
principal investigator 
PK 
pharmacokinetic 
PLT 
platelet 
PSQI 
Pittsburgh Sleep Quality Index 
QD  
quaque die (once daily) 
RBC 
red blood cell 
RDW  
red blood cell distribution width 
SAE  
serious adverse event 
SERM 
selective estrogen receptor modulator 
SNRI 
serotonin norepinephrine reuptake 
inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
SC 
subcutaneous 
TNF-alpha 
tumor necrosis factor-alpha 
TSH 
thyroid stimulating hormone 
U 
units 
US 
United States 
WBC 
white blood cell 
WHI  
Women’s Health Initiative 
 

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1 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
Prior to trial initiation, the Investigator at each site must provide to MenoGeniX, Inc. 
(MenoGeniX), a protocol signature page, a Financial Disclosure Form, FDA Form 1572 and 
documentation of Institutional Review Board (IRB) approval. 
The trial will be administered and monitored by employees or representatives of 
MenoGeniX. The Clinical Research Associates (CRAs) will monitor each site on a periodic 
basis and perform verification of source documentation for each subject. MenoGeniX will be 
responsible for ensuring timely reporting of expedited Serious Adverse Event (SAE) reports 
to regulatory agencies, IRB, and Investigators, as applicable by local regulations. 
 
 

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2 
INTRODUCTION 
A comprehensive review of filgrastim (recombinant methionyl human granulocyte colony-
stimulating factor [r-metHuG-CSF], marketed by Amgen under the trademark Neupogen® 
and generic name filgrastim) is contained in the Investigator’s Brochure. This document 
should be reviewed prior to initiating the study. 
2.1 
Background Therapeutic Information 
G-CSF is being developed for the treatment of hot flashes and other vasomotor symptoms 
associated with natural, surgical or chemically-induced menopause. Up to 86% of all 
naturally menopausal women consult a doctor during their menopausal transition to discuss 
symptom management [1]. The primary symptom that triggers a woman to seek treatment 
during her menopausal transition is the hot flash. Symptoms appear to be more prevalent and 
severe in women who have undergone hysterectomy with bilateral oophorectomy (surgical 
menopause), have premature menopause [2] or are on Tamoxifen or aromatase inhibitors for 
the treatment of breast cancer. A similar proportion of men who undergo androgen ablation 
therapy for prostate cancer will also report hot flashes [3]. Although hot flashes subside over 
time for the majority of women who are affected, 16% have been reported to remain 
symptomatic 4-5 years past their final menstrual period [4] and ~2% of untreated women in 
their 70’s report experiencing hot flashes or night sweats [5].  
Hormone therapies (HTs) consisting of estrogens or estrogens plus progesterone are the only 
approved medications to treat hot flashes. However, as described in Section 2.2, there is 
much confusion and concern about the use of HT to safely treat these symptoms [6,7]. An 
effective, non-hormonal treatment for hot flashes and related vasomotor symptoms would be 
a welcome, novel and useful treatment modality.  
Evidence exists that a single, 300 mcg (~5 mcg/kg), subcutaneous (SC) injection of G-CSF 
(as Neupogen®) administered to assess cyclic neutropenia in a menopausal woman resulted in 
a significant and long-term (approximately 3-month) reduction in hot flash frequency and 
severity. A second single 300 mcg administration of G-CSF (as Neupogen®) to the same 
individual ~3 years later resulted in a similar 3-month diminution in hot flash frequency and 
severity. This anecdotal observation led to a confirmatory, 12-week, randomized, placebo-
controlled, phase 1 clinical trial in 30 women with naturally-occurring and surgically-induced 
menopause which showed that a single non-weight-adjusted, 275 mcg dose of G-CSF (mean 
dose = 3.9 mcg/kg; range = 3.1 – 5.3 mcg/kg) resulted in a statistically significant reduction 
in hot flash frequency and severity through three weeks post administration with 37% of the 

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G-CSF-treated women reporting greater than 50% reduction in hot flashes by 2 weeks and 
70-85% reduction at 12 weeks post-administration.   
2.2 
Background and Significance 
Hot flashes occur in over 75% of women who are traversing menopause and they persist in 
up to 16% of women more than a decade after menopause [4,8]. Hormone therapy is the only 
FDA-approved therapy for the treatment of moderate to severe menopausal symptoms. 
Hormone therapy is highly effective and was approved based on its reported efficacy in 
reducing hot flash frequency in post-menopausal women by 70 – 90% [2,4].  However, 
results from the Women’s Health Initiative (WHI) study published in 2002, resulted in 
significant “boxed” warnings about HT use including an increased risk of developing cancer, 
heart disease, stroke, and dementia [6,7]. In addition, HT is contraindicated for women with 
breast cancer and for survivors of breast cancer undergoing estrogen suppression, and may 
not be appropriate for those women who undergo bilateral oophorectomy because of a 
genetic susceptibility to develop breast or cervical cancer (BRCA1 and/or BRCA2 positive). 
Finally, HT is an inappropriate treatment for hot flashes due to other causes (e.g., in men with 
prostate cancer undergoing androgen ablation).  
The current indications for HT are a relationship between menopause and hot flashes (hot 
flashes/night sweats), sleep disturbances, and mood disorders [8,9]. Both the physiological 
mechanisms underlying a hot flash and the exact mechanism of action of HT in alleviating 
menopausal symptoms remain unknown.  
Due to the published serious health risks and boxed warnings associated with HT [6,7], 
several non-hormonal alternatives are often prescribed for off-label use by healthcare 
providers. The current non-hormonal alternative to HT that is approved is BrisdelleTM. In 
2013, the FDA approved BrisdelleTM, a low dose version of the anti-depressant paroxetine, 
for the treatment of moderate to severe vasomotor symptoms associated with menopause. 
Additionally, other non-hormonal alternatives to HT and paroxetine that are not approved for 
this use but which have shown a limited degree of efficacy in recent clinical studies include 
antidepressants such as the selective serotonin reuptake inhibitor (SSRI) and serotonin 
norepinephrine reuptake inhibitor (SNRI) classes of drugs (e.g., venlafaxine, paroxetine, 
fluoxetine, citralopram, escitalopram) and the anti-epilepsy pain medication gabapentin [10]. 
The former drug class can cause significant side effects, including addiction and severe 
withdrawal symptoms while gabapentin is limited in daytime use by its chief side effect, 
drowsiness. Anti-depressants and gabapentin have less than half the effectiveness of HT [11]. 
Treatment with nutraceuticals has also been investigated and found to be non-effective. In 

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summary, there are no alternative non-hormonal treatments currently under development that 
match HT’s demonstrated efficacy in reducing the frequency and/or severity of hot flashes.  
2.3 
G-CSF 
Human granulocyte colony-stimulating factor (G-CSF) is currently indicated to stimulate the 
proliferation and differentiation of granulocytes. G-CSF is available in the US as Neupogen®, 
TevaGrastim® and Zarxio®. Neupogen® is the Amgen Inc. trade name for filgrastim‚ 
recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF), 
synthesized in bacteria. TevaGrastim® is the Teva Pharmaceuticals trade name for filgrastim. 
Zarxio® is the Sandoz, a Novartis company, trade name for filgrastim.  Both TevaGrastim® 
and Zarxio® are approved as Neupogen® biosimilars. Since filgrastim is produced in bacteria, 
it differs slightly from that of the naturally produced human G-CSF.  
G-CSF is given daily to cancer patients during the course of chemotherapy and life-long to 
those with chronic severe neutropenia [12]. G-CSF, normally produced in healthy individuals 
in response to infections, stimulates the production of a subset of white blood cells (WBC). 
This subset of cells, including neutrophils, basophils, and eosinophils, is collectively referred 
to as granulocytes and is involved in fighting infections caused by bacteria, fungi and 
parasites. Although all WBCs are derived from precursor cells in the bone marrow, 
granulocytes, in particular, have a very short life span and are regenerated constantly. Certain 
chemotherapy regimens damage these precursor cells in the bone marrow resulting in low 
WBC counts, a condition referred to as neutropenia. Chronic neutropenia is also observed in 
rare individuals that are born with the disease (congenital) or who develop the disease for 
unknown reasons (idiopathic), the latter of which can also be cyclic. When neutrophil cell 
counts drop to a very low level, patients become susceptible to severe, life-threatening 
bacterial infections. 
A factor that stimulated neutrophil growth was first described in 1967 by Drs. Metcalf, 
Robinson, and Bradley at the Walter and Elisa Hall Institute in Melbourne [13]. The mouse 
protein was purified in 1983 by Metcalf and colleagues and the human gene was cloned in 
1986 by two additional groups of researchers, eventually resulting in the FDA-approved 
version of recombinant human G-CSF. G-CSF, which increases peripheral granulocytes and 
precursors in humans over 5 to 7 days, is used for the treatment of oncology patients to 
accelerate recovery from chemotherapy-induced neutropenia allowing for higher-intensity 
treatment regimens in breast cancer in particular. G-CSF, marketed under the trade name 
Neupogen®, was first approved in 1991 to decrease the incidence of bacterial infection, as 
manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving 

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myelosuppressive anti-cancer drugs. Additional market approvals were later granted for the 
reduction of incidence and sequalae of low WBC counts in symptomatic children and adults 
with congenital, cyclic, or idiopathic severe neutropenia.  
G-CSF has been used successfully both chronically in patients with idiopathic neutropenia 
over several years and as a burst therapy (daily use for up to 14 days) in patients with 
chemotherapy-induced neutropenia [14]. To date, over 9 million patients have received 
G-CSF therapy [13]. Meta-analysis of studies shows a 46% decrease in febrile neutropenia 
and 40% decrease in early mortality. The demonstration of such robust efficacy has led to 
physician recommendations of its use as a prophylactic measure when risk of neutropenia is 
>20% [13]. Cost is the major limitation to increased widespread use [13]. The most common 
side effect with repeated injections is bone pain due to expansion of bone marrow cell 
populations [15]. Bone pain was reported more frequently in patients treated with high 
intravenous (IV) doses (20 to 100 mcg/kg/day)‚ and less frequently in patients treated with 
lower SC doses of Neupogen® (3 to 10 mcg/kg/day) [16]. 
Due to the low toxicity of G-CSF that has been observed in animal models and in extensive 
clinical experience with neutropenic patients, additional clinical studies in non-neutropenic 
subjects have been undertaken and have shown G-CSF treatment to be safe, beneficial and 
well tolerated for the prevention and/or treatment of infections in patients at high risk of 
infection undergoing surgery, those with HIV, and with diabetic foot ulcers [17,18]. G-CSF 
has also been used to aid expansion of bone marrow precursor cells after marrow 
transplantation and to expand peripheral blood stem cells in healthy human donors [19].  
Beyond its obvious effects on bone marrow, G-CSF also acts as a growth stimulating and 
survival factor for neurons. The G-CSF receptor is expressed by neurons in the brain and 
spinal cord which, upon activation, induces growth of nerve cells and increases 
neuroplasticity. Of interest, estrogen has also been reported to have neurotrophic effects. 
Basic studies have examined the effects of G-CSF on neuroprotection and neural repair and 
survival. Current clinical investigations are exploring the role of G-CSF in ischemic stroke 
and in spinal cord injury [20].  
The G-CSF receptor is also expressed widely in endothelium cells and throughout the 
reproductive system. In this regard, G-CSF has shown some potential in human clinical trials 
to induce beneficial angiogenesis in cardiovascular disease and to prevent recurrent 
miscarriages [21]. These studies are on-going and no version of G-CSF is currently approved 
for any indication other than to prevent febrile disease in chemotherapy-induced, congenital 

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or idiopathic severe neutropenia. Nonetheless, these studies suggest that G-CSF may have 
effects beyond stimulation of granulocyte precursors.  
As the mechanisms underlying hot flashes are poorly understood, it is difficult to postulate a 
potential mechanism of how administration of G-CSF would alleviate them. Additional 
clinical investigation of G-CSF may lead to identification and characterization of this 
mechanism, and eventually to an effective alternative to HT for the treatment of subjects 
suffering these symptoms.  
2.4 
Safety Experience with G-CSF 
The current study proposes to subject thirty healthy postmenopausal women to three single, 
subcutaneous injections of G-CSF at 28 day intervals (300 mcg).  
As described in the Investigator’s Brochure and in the Neupogen® package insert, filgrastim 
was administered to monkeys, dogs, hamsters, rats and mice as part of a preclinical 
toxicology program which included single-dose acute‚ repeated-dose subacute‚ subchronic‚ 
and chronic studies. Single-dose administration of filgrastim by the oral‚ IV, SC or IP routes 
resulted in no significant toxicity in mice‚ rats‚ hamsters‚ or monkeys at doses as high as 
3450 mcg/kg in mice, rats and monkeys.  
 
 
 

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2.4.1 
Previous G-CSF Experience in Phase 1 Single-Dose Healthy Volunteer 
Studies 
Since its approval by the FDA in 1991, G-CSF has been administered chronically to more 
than 9 million individuals with chemotherapy-induced, congenital, and idiopathic severe 
neutropenia [13]. The common side effects and AEs described for G-CSF are associated with 
chronic daily use in the setting of chemotherapy-induced, congenital, and idiopathic severe 
neutropenia at daily dosage levels that often exceed the single SC dose to be administered in 
this proposed clinical trial (300 mcg per subject, given once). The following Phase 1 study 
summaries are included to give background clinical experience from studies investigating 
single injection doses of G-CSF in healthy volunteers. 
2.4.1.1 
Amgen Neupogen® Phase 1 (Healthy volunteer; Single dose) 
The following Phase 1 study was the only single dose, healthy volunteer study conducted by 
Amgen prior to advancing filgrastim directly into their target chemotherapy induced 
neutropenic population.   
A Phase 1 single-dose, placebo-controlled study in 21 normal healthy volunteer males was 
conducted to determine the safety, pharmacodynamic (PD) effects, and pharmacokinetic (PK) 
profile of filgrastim [22].  
Intravenously administered filgrastim resulted in a dose-dependent and rapidly reversible 
increase in absolute neutrophil counts (ANC) when administered as single doses in a range of 
0.575 – 3.45 mcg/kg. Filgrastim was well tolerated with no clinically important AEs 
recorded. Filgrastim showed first order pharmacokinetics with an elimination half-life of 
160 minutes.  
The effect of filgrastim on increasing ANC was highly specific. Minor increases seen in 
monocyte, eosinophil, basophil, and WBC precursor counts were clinically insignificant. The 
most frequently reported AE was bone pain, which was generally mild to moderate in 
severity.  
2.4.1.2 
Biosimilar AVI-014 and Neupogen® Phase 1 (Healthy volunteer; Single dose) 
AVI-014 is a chicken egg white-derived, recombinant, human (G-CSF). This healthy 
volunteer study was the first human investigation of AVI-014 [23]. 
Twenty-four male and female subjects received a single subcutaneous injection of AVI-014 
at 4 or 8 mcg/kg. Sixteen control subjects received 4 or 8 mcg/kg of Neupogen® in a partially 
blinded, parallel fashion. All subjects completed the trial. The age range of subjects was 21-

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50. There were no serious adverse events (SAEs) reported during the study. A total of 47.5% 
of the enrolled subjects experienced at least one AE. Of a total of 42 AEs, thirty-four events 
were assessed as possibly related to study drug. The most common adverse events were 
headache, myalgia, back pain, and bone pain. Fifty percent (12 of 24) of subjects treated with 
AVI-014 and 43.8% (7 of 16) of those treated with Neupogen® experienced an AE. 
Musculoskeletal complaints, which included bone pain and muscle aches, occurred in 37.5% 
(9 of 24) subjects receiving AVI-014 and 18.8% (3 of 16) of subjects receiving Neupogen®.  
Headache occurred in 20.8% (5 of 24) subjects receiving AVI-014 and 18.8% (3 of 16) of 
subjects receiving filgrastim.  
2.4.1.3 
Biosimilar Nivestim™ and Neupogen® Phase 1 (Healthy Volunteer; Single 
Dose) 
This was a Phase 1, single-center, open-label, randomized trial designed to evaluate and 
demonstrate equivalence between the PK characteristics of Hospira manufactured filgrastim 
(NivestimTM) and Amgen manufactured filgrastim [24].  
Forty-eight healthy volunteers (male and female, aged 18 – 45 years) were randomized to 
receive IV or SC dosing and then randomized to order of treatment. Volunteers in each of the 
two dosing groups received a single 10 mcg/kg dose of Hospira filgrastim or Amgen 
filgrastim, with subsequent crossover to the opposite arm. Forty-six volunteers completed the 
study.  
No significant differences in AE profiles were observed between Hospira filgrastim and 
Amgen filgrastim. The overall incidence of AEs was lower in volunteers who received IV 
Hospira filgrastim compared with those who received IV Amgen filgrastim; however, similar 
incidences of AEs were reported between volunteers in both arms who received study drugs 
via the subcutaneous route. The most commonly reported AEs included headache, back pain, 
and nausea. All AEs were mild or moderate in intensity and no SAEs were reported. No 
clinically significant changes in heart rate, 12-lead ECG, hematology, biochemistry, 
urinalysis, or changes in physical examination were reported.  
2.4.1.4 
Biosimilar Zarzio® and Neupogen® Phase 1 (Healthy Volunteer; Single and 
Multiple Doses) 
Zarzio®, a recombinant G-CSF (filgrastim), has been evaluated in healthy volunteers and 
neutropenic patients in Phase 1 and 3 studies [25]. Healthy volunteers (male and female) in 
randomized, two-period crossover studies received single- and multiple-dose SC injections of 
1 mcg/kg (n = 24), 2.5 mcg/kg (n = 28), 5 mcg/kg (n = 28), or 10 mcg/kg (n = 40), as well as 

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single-dose IV infusions of 5 mcg/kg (n = 26), of Zarzio® or the reference product 
(Neupogen®). Filgrastim serum levels were monitored; PD parameters included absolute 
neutrophil count (all studies) and CD34+ cells (multiple dose studies). Safety assessments in 
the Phase 1 studies consisted of monitoring and recording all AEs and SAEs, assessments of 
physical condition, vital signs, electrocardiogram, and monitoring of laboratory values. Local 
tolerance was evaluated by self-assessment of the subjects using a visual analog scale and by 
the investigators using the injection site reaction score. 
In the Phase 1 crossover studies, 146 healthy volunteers (81 males and 65 females, ages     
21-54 years) were treated with Zarzio® and Neupogen®. Study drug-related AEs frequently 
observed in healthy volunteers under Zarzio® or Neupogen® treatment were as expected (mild 
to moderate musculoskeletal pain, leukocytosis, thrombocytopenia, and headaches). There 
were no clinically-relevant differences between Zarzio® and Neupogen® in the frequency or 
type of AEs by system organ class and severity (all generally mild or moderate). No SAEs 
were observed and no deaths occurred during any of these studies. Results from the 
laboratory tests, vital signs measurements, and physical examinations confirmed the absence 
of marked changes in the subjects’ state of health.  
In summary, the combined results of these healthy volunteer studies are reflective of the 
already established mild toxicity of Neupogen®, especially as relevant to a single SC 
injection, and as characterized in multiple large randomized trials as well as a large post-
marketing safety database. 
2.4.2 
Previous G-CSF Experience in Chemotherapy-induced, Congenital and 
Idiopathic Severe Neutropenia 
As described previously, as well as in the Neupogen® (filgrastim) package insert and in the 
Investigator’s Brochure, G-CSF has been chronically administered to millions of individuals 
subcutaneously (4 – 8 mcg/kg/day) as well as intravenously (5 – 10 mcg/kg/day). Clinical use 
in these settings has shown the drug to be safe, well tolerated, and uniformly efficacious in 
raising circulating granulocyte cell counts. The most common adverse events (AEs) that were 
consistently reported in phase 2 and phase 3 clinical trials of Neupogen® for neutropenic 
conditions included mild to moderate bone pain (24 – 33%) and headache (<10%); both were 
readily controlled by non-narcotic analgesics [16]. Bone pain was reported more frequently 
in patients treated with higher doses (20 to 100 mcg/kg/day) administered IV, and less 
frequently in patients treated with lower SC doses of Neupogen® (3 to 10 mcg/kg/day) [16]. 
Allergic-type reactions occurring on initial or subsequent treatment have been reported in <1 
in 4000 patients treated with Neupogen®. Reactions tended to occur within the first 

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30 minutes after administration and appeared to happen more frequently in patients 
administered IV Neupogen®. Rapid resolution of symptoms occurred in most cases following 
administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine. 
The following adverse reactions were identified during post-approval of Neupogen®: splenic 
rupture; acute respiratory distress syndrome (ARDS); alveolar hemorrhage and hemoptysis, 
sickle cell crisis; cutaneous vasculitis; and Sweet’s syndrome (acute febrile neutrophilic 
dermatosis). Because these reactions are reported voluntarily from a population of large, but 
uncertain size, it is not always possible to reliably estimate their frequency or establish a 
causal relationship to drug exposure.  
2.5 
Background and Rationale for the Current Study 
2.5.1 
Clinical Study MNGX-101: A Randomized, Double-Blind, Placebo-
Controlled Pilot Phase 1b Study to Assess the Safety and Effect of a Single 
Subcutaneous Dose of Granulocyte Colony-Stimulating Factor (G-CSF; 
filgrastim) to Treat Hot Flashes in Postmenopausal Women 
MXGX-101 was a 12-week multicenter, double-blind, placebo-controlled, study to evaluate 
the safety and effect of a single, non-weight adjusted, 300 mcg, SC injection of G-CSF (mean 
dose = 3.9 mcg/kg; range = 3.1 – 5.3 mcg/kg) in women who were experiencing 
postmenopausal hot flashes. Subjects were stratified by natural or surgical menopause and 
randomized (2:1) to receive either G-CSF or placebo. The study enrolled female subjects 
aged 50 to 65 who were postmenopausal and experiencing at least 7 moderate to severe hot 
flashes per day on average, or at least 49 moderate to severe hot flashes per week. G-CSF 
was provided as Neupogen® packaged in individual 1.0 mL vials containing 300 mcg 
filgrastim. A single subcutaneous injection, in the outer area of either upper arm, of G-CSF 
(300 mcg) in a total volume of 1 mL was given at Baseline to subjects randomized to receive 
G-CSF. The women kept daily diaries recording the number of mild, moderate and severe hot 
flashes that they experienced for the subsequent 84 days post administration. A total of 30 
subjects were enrolled in the study, 11 in the placebo group and 19 in the G-CSF treatment 
group. All subjects completed the study and were included in the Intent-to-Treat (ITT) and 
Safety populations. 
The primary objective of this pilot study was to describe the effect of a single subcutaneous 
injection of G-CSF on the frequency and severity of hot flashes in postmenopausal women. 
The secondary objectives of this pilot study were to assess additional measures of hot flash 
burden, circulating hormone and inflammatory cytokine concentrations, and safety. 

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In patients with frequent hot flashes at baseline (>7 moderate + severe per day), a single 
injection of G-CSF at time 0 resulted in a statistically significant efficacy signal at week two 
post-administration compared to placebo. Specifically, a statistically significant reduction 
from baseline was observed at two weeks in:  
1) Mean daily total hot flashes (mild + moderate + severe) (35% reduction in the G-
CSF group vs. 5% reduction in the placebo; p=0.016);  
2) Mean daily moderate plus severe hot flashes (36% reduction in the G-CSF group 
vs. 5% reduction in the placebo; p=0.013) (see Figure 3);  
3) Mean daily severe hot flashes (46% reduction in the G-CSF group vs. 27% 
increase in the placebo; p=0.019);  
4) Mean composite daily hot flash score ((1 x mild)+(2 x moderate)+(3 x severe) 
(39% reduction in the G-CSF group vs. 1% reduction in the placebo; p=0.015); 
and  
5) Mean daily hot flash severity score (0.23 unit lessening of severity in the G-CSF 
group vs. 0.08 unit worsening in the placebo group; p=0.002) (see Figure 4) 
This strong effect was highly significant when the modest number of subjects (n=29) is 
considered.  
A leveling-off of response was observed in the treated group after week 3 which is consistent 
with the known pharmacological effects of G-CSF in the setting of neutropenia clearance and 
effect on circulating neutrophil cell counts); however, we also observed an unexpected 
reduction in hot flash frequency but not severity in the placebo group starting at week 4.  
 
 
 
 
 
 
 
 

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Retrospective analysis of the data, focusing on the 2 week time point revealed that 37% (7 
out of 19) of the treated subjects vs. none (0 out of 10) of the placebo subjects reported a 
greater than 50% reduction in total hot flash frequency and a greater than 55% reduction in 
moderate + severe hot flashes and composite daily score (p=0.032) (see Figure 6). Weight-
adjusted dose did not predict “high” responders and this “potential threshold effect” will 
require further research. This finding suggests the possibility that there may be a threshold 
dose which is required to elicit a response and implies that a higher dose or more frequent 
dosing may be effective in a higher percentage of subjects. It should be further noted that the 
reduction in hot flash frequency and severity reported by the treated subjects at 2 weeks 
provided a reasonable prediction of their response at 12 weeks in terms of improvement in 
hot flashes and QOL whereas the placebo response at 2 weeks was not predictive.  
Summary of Adverse Events in MNGX-101 
Adverse Event 
 
Placebo 
(n=11) 
MNGX-100 
(n=19) 
All 
(n=30) 
n 
% 
n 
% 
n 
% 
Common Gastrointestinal Distress 
1 
9 
2 
11 
3 
10 
Ulcerative colitis 
0 
0 
1 
5 
1 
3 
Headache 
4 
36 
7 
37 
11 
37 
Musculoskeletal pain 
3 
27 
4 
21 
7 
23 
Clenching Jaws 
0 
0 
1 
5 
1 
3 
Common Respiratory Ailments 
4 
36 
8 
42 
12 
40 
Left chest pain 
1 
9 
0 
0 
1 
3 
Nosebleed 
0 
0 
1 
5 
1 
3 
Menstrual cramps and spotting 
1 
9 
1 
5 
1 
3 
Fatigue 
1 
9 
1 
5 
2 
7 
Elective surgery 
0 
0 
2 
11 
2 
7 
Dizziness 
1 
9 
0 
0 
1 
3 
Pruritus 
0 
0 
1 
5 
1 
3 
Bone pain 
0 
0 
0 
0 
0 
0 
 

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2.5.2 
Original Case Study  
A 52-year old female experienced onset of menopause with severe, frequent hot flashes. Due 
to a family history of breast cancer and personal preferences, the subject declined hormonal 
therapy. The hot flashes occurred both day and night, and were disruptive to the subject’s 
sleep and daily activities at home and at work. She was otherwise healthy. In her annual visit 
to her physician she was noted to have persistently low WBC (range 2.9 – 3.5 x109/L) and 
ANC (1.3 – 1.5 x 109/L) counts (normal reference ranges are 4.0 – 11.1 x 109/L and 1.8 – 7.8 
x 109/L respectively). She was evaluated by a hematologist at the University of Colorado for 
cyclic neutropenia and, after exclusion of other etiologies by her physician, was given a 
single injection of Neupogen® (300 mcg/SC). Within four days her WBC and ANC counts 
increased into the normal reference range (4.1 x 109/L; 2.4 x 109/L) and returned to pre-
treatment levels by 30 days (3.1 x 109/L; 1.4 x 109/L). The only AE experienced after the 
injection was a transient mild tingling sensation, of short duration. Five to seven days after 
the injection she noted a dramatic decline in the frequency and severity of her hot flashes. 
This alleviation of her symptoms persisted for approximately 3 months, despite the absence 
of other changes in weight, dietary supplements, or medications. Because the effect was so 
dramatic, the literature was reviewed, and no obvious explanation was found. Approximately 
three years later, she received another single injection of Neupogen® (300 mcg/SC). 
Before receiving the second injection, she monitored her daily hot flash frequency and 
severity. As previously noted, beginning at five to seven days following the injection, the 
frequency of her hot flashes again dramatically decreased by approximately 75%. A daily 
diary was kept for 30 days (see Figure 1) and for approximately the next 2 months, she noted 
that her hot flashes were much less frequent and much less bothersome. The hot flashes 
gradually returned to the pre-treatment level approximately 3 months after the injection. She 
also noted that her hot flashes were much less bothersome, and her joint and muscle pain had 
improved. Again, the only AE experienced after the injection was a transient mild tingling 
sensation, of short duration. 
 
 
 
 
 

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Brisdelle® and other neuroactive anti-psychotic, anti-depression and pain drugs that are often 
prescribed off-label carry their own significant health risks and they appear to be prescribed 
mainly because of the perceived risks of HT. The following information summarizes the 
boxed warnings, warnings and precautions that are described in the prescribing information 
for the HT Premarin®.  
Boxed Warnings for HT: Risk of development of endometrial cancer; cardiovascular 
disease; breast cancer; and dementia. 
Warnings for HT: See boxed warnings plus: cardiovascular disorders including stroke, 
coronary heart disease and venous thromboembolism; malignant neoplasms including 
endometrial, breast and ovarian cancers; probable dementia; gallbladder disease; 
hypercalcemia; visual abnormalities; anaphylactic reactions and angioedema; and 
exacerbation of hereditary angioedema. 
Precautions for HT: Elevated blood pressure; hyperglyceridemia; hepatic impairment; 
hypothyroidism; fluid retention; hypocalcemia; exacerbation of endometriosis; and 
exacerbation of asthma, diabetes, epilepsy, migraine, porphyria, SLE, and hepatic 
hemangiomas.  
Since publication of the Women’s Health Initiative in 2002, use of HT has declined greatly 
due to the published health risks.  
The following information summarizes the boxed warnings, warnings and precautions that 
are described in the prescribing information for the HT BrisdelleTM.  
BrisdelleTM, is a low dose version of the anti-depressant paroxetine, approved for the 
treatment of moderate to severe vasomotor symptoms associated with menopause (REF). 
BrisdelleTM was approved despite a 10-4 vote against approval by the Advisory Committee 
due to safety concerns and lack of efficacy. It showed less than half the efficacy of HT after 
24 weeks of daily dosing in terms of reduction of hot flash frequency and almost no reduction 
in hot flash severity (REF). The following information summarizes the boxed warnings, 
warnings and precautions that are described in the prescribing information for BrisdelleTM 
(REF).   
Boxed Warnings for BrisdelleTM: Potential for increased risk of suicidal thinking and 
behavior. Monitor for worsening or emergence of suicidal thoughts and behaviors. 
Warnings for BrisdelleTM: See boxed warnings plus: development of serotonin syndrome 
alone but particularly with concomitant use of serotonergic drugs; potential impact on 

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tamoxifen efficacy; abnormal bleeding; hyponatremia; bone fracture; requirement to screen 
patients for bipolar disorder and monitoring for mania/hypomania; seizures; akathisia; acute 
angle closure glaucoma and potential for cognitive and motor impairment. 
Although millions of oncology and other severely neutropenic patients have received 
treatment with filgrastim since Neupogen was approved in 1991, there have been no clinical 
studies to date specifically investigating filgrastim in women who are experiencing 
postmenopausal hot flashes. Therefore, available data from clinical trials where filgrastim 
was administered to healthy volunteers provides the most relevant clinical experience data for 
the current patient population. Safety data obtained from trials in cancer patients and other 
patient populations are also included for reference information.  
Based on data available from Phase 1 through Phase 3 clinical trials, including head-to-head 
comparison studies in healthy volunteers, and from a post-marketing safety database of over 
9 million neutropenic patients, G-CSF administered as a single dose to postmenopausal 
women is expected to be very well tolerated, with no significant adverse reactions. On the 
basis of currently available data, G-CSF appears to have reproducible biologic activity and an 
acceptable short-term safety profile in normal subjects. The common adverse events consist 
mainly of bone pain, headache, fatigue and nausea. Anxiety, noncardiac chest pain, myalgias, 
insomnia, night sweats, skin rashes, anorexia, dizziness, weight gain, local reactions at the 
injection site, and vomiting have occasionally been reported as well. Of interest, G-CSF-
related fever has been rarely reported. Clinically relevant drug interactions between G-CSF 
and other drugs have not been reported.  
The warnings and precautions regarding the clinical use of G-CSF apply to the setting of 
chemotherapy-induced, congenital and idiopathic severe neutropenia and involve multiple 
daily injections over extended periods of time. Based on current available healthy volunteer 
data with a single SC injection, where serious safety events were not observed, most of the 
warnings/precautions observed with chronic administration are much more serious than what 
is expected in a healthy postmenopausal woman following a single injection of G-CSF.  
Potentially relevant side effects with a single SC injection of G-CSF include sensitivity at the 
injection site, bone pain, muscle aches, and headaches. Unlike HT and paroxetine, G-CSF 
does not have a black box warning. The safety profile of three, 4-week repeated injections of 
G-CSF in post-menopausal women compares reasonably well with the safety profile of short-
term HT use in this same population.  

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2.5.4 
Dose Selection 
The recommended starting dose of Neupogen® in cancer patients receiving myelosuppressive 
chemotherapy is 5 mcg/kg/day‚ administered as a single daily injection by SC bolus 
injection‚ short IV infusion (15 to 30 minutes)‚ continuous SC infusion, or continuous IV 
infusion. 
Cancer patients receiving bone marrow transplant (BMT) have a recommended dose of 10 
mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. 
When used for peripheral blood progenitor cell collection (PBPC) and therapy in cancer 
patients, the recommended dose is 10 mcg/kg/day SC‚ either as a bolus or a continuous 
infusion. 
The recommended daily starting dose for congenital neutropenia is 6 mcg/kg BID SC while 
the recommended daily starting dose for idiopathic or cyclic neutropenia is 5 mcg/kg as a 
single injection SC QD (once daily). 
The current study proposes to subject thirty healthy postmenopausal women to three single, 
subcutaneous injections of 300 mcg G-CSF at 28 day intervals.  
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3 
STUDY OBJECTIVES  
The primary objective of this Phase 1b study is to assess the safety and pharmacodynamic 
(PD) effects of three single subcutaneous injection(s) of 300 mcg G-CSF administered at 28 
day intervals in healthy menopausal women.  
The secondary objectives of this proposed study are to assess the efficacy of three single 
subcutaneous injection(s) of 300 mcg G-CSF administered at 28 day intervals in reducing the 
frequency and severity of hot flashes in postmenopausal women and to assess additional 
measures of hot flash burden. 
 
 

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4 
STUDY DESIGN AND PLAN 
This is a 12-week, multicenter, double-blind, placebo-controlled study. Eligible subjects will 
be stratified by natural or surgical menopause and randomized (1:1) to receive three 
injections, 28-days apart, of either 300 mcg G-CSF or placebo.  
Subjects enrolled will be given three single 1.0 mL SC injections (repeated 28-days apart), in 
the outer area of either upper arm, of either G-CSF or placebo (sterile physiological saline) at 
Baseline, Day 28 and Day 56. Subjects will be followed for 12 weeks and will complete hot 
flash diary entries every day for the duration of treatment. Safety will be assessed by adverse 
events, clinical laboratory tests (clinical chemistry and CBC with differential) and vital signs.  
The study will have an independent Data Safety Reviewer assigned by the NIH to review 
safety data at regular intervals. 
4.1 
Treatment Plan and Regimen 
4.1.1 
Treatment Plan 
In total, 65 subjects will be enrolled in this study.  
4.1.2 
Dose, Time of Administration and Duration of Treatment 
Subjects randomized to receive the active treatment dose of G-CSF will be given one 1.0 mL 
SC injection at Baseline, Day 28 and Day 56, prepared from an individual 1.0 mL vial 
containing 300 mcg G-CSF. Subjects randomized to receive placebo will be given one 1.0 
mL SC injection at Baseline, Day 28 and Day 56 prepared from an individual vial of sterile, 
physiological, preservative free, isotonic saline (placebo), at the clinical investigational site. 
Treatment with G-CSF or placebo will be given three times, 28-days apart, as a single SC 
injection in the outer area of either upper arm at Baseline, Day 28 and Day 56. 
The study duration is 12 weeks and subjects will continue unless they meet any of the criteria 
for discontinuation (see Section 7.3). 
4.2 
End of Study 
The end of the study will be deemed as the date of the last visit of the last subject 
participating in the clinical trial.  
4.3 
 NIH-assigned Data Safety Reviewer Board 
The NIH assigned Data Safety Reviewer will be responsible for reviewing safety data at 
regular intervals.  

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5 
SUBJECT POPULATION 
Questions regarding eligibility criteria should be addressed with MenoGeniX PRIOR to 
randomization of the potential subject. Eligibility criteria are standards required to ensure that 
subjects who enter this study are medically appropriate candidates for treatment with G-CSF. 
5.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study. 
1. Female, aged 49 to 65 for naturally postmenopausal and aged 40 to 65 for surgically 
postmenopausal; 
2. Body Mass Index (BMI) 18 to 35; 
3. At least 7 moderate to severe hot flashes per day on average (or 49 moderate to severe hot 
flashes per week); 
4. Naturally postmenopausal or surgically postmenopausal: 
a. Naturally postmenopausal is defined as having no menstrual periods for at least 12 
months prior to study entry; with a biochemical criteria of menopause (FSH ≥  the 
reference range for menopause for the local laboratory used for screening); 
b. Surgically postmenopausal is defined as at least 3 months after documented 
bilateral salpingo oophorectomy; 
5. Normal pelvic exam within 2 years; 
6. Normal pap smear within 2 years (if uterus/cervix were present); and 
7. Signed informed consent. 
5.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
1. Radiation or chemotherapy-induced (including GnRH agonist) menopause; 
2. Prior chemotherapy or radiation therapy for cancer; 
3. Prior diagnosis of hematologic malignancy; 
4. Type 1 diabetics or Type 2 diabetics with HbA1c > 7.0%; 
5. Use of hormone replacement therapy or oral contraceptives within the past three months; 

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6. Use of alternative or complementary medicines or herbs for menopausal symptoms 
within 30 days (refer to Appendix 2 for list of exclusionary drugs/supplements); 
7. Use of any SSRI or SNRI within 30 days; 
8. Use of selective estrogen modulators within 30 days; 
9. Use of gabapentin within 30 days; 
10. Use of clonidine within 30 days; 
11. Use of megestrol acetate (Megace) within 30 days; 
12. Use of prescription corticosteroids within 30 days (nasal or other inhaled corticosteroids 
and OTC topical corticosteroids excepted); 
13. Current use of lithium therapy (related to possible risk of G-CSF); 
14. History (in the past year) or presence of drug or alcohol use which, in the opinion of the 
Investigator, might compromise the study or confound the study results; 
15. History of use of any anti-inflammatory biologics ; 
16. History of or current splenomegaly (related to possible risk of G-CSF); 
17. History of sickle cell disease (related to possible risk of G-CSF); 
18. High risk for medical complications that might affect the subject’s ability to complete the 
trial without a serious co-morbid event, based on medical history, physical examination 
and laboratory screening evaluation in the opinion of the Investigator; 
19. Presence of an acute or chronic condition (such as a hematological, rheumatologic auto-
immune disease, chronic inflammatory disorder, chronic lung disease or osteoporosis) 
based on history, clinical, or laboratory evaluation, which, in the opinion of the 
Investigator, might compromise the study, confound the study results or place the subject 
at risk;  
20. Follicle stimulating hormone (FSH) below the reference range for menopause for the 
local laboratory used for screening 
21. Thyroid stimulating hormone (TSH) outside normal limits at study entry; 
22. Absolute neutrophil count (ANC) ≤ 1.0 x 109/L; 
23. Total white blood cell count (WBC) ≤ 3.0 x 109/L; 
24. Platelet count (PLT) ≤ 150 x 109/L;  
25. Hemoglobin count (HGB) consistent with anemia;  
26. Positive urine pregnancy test at Baseline visit; 

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27. Allergy or hypersensitivity to E coli-derived proteins‚ G-CSF‚ or any component of the 
product; 
28. Mentally or legally incapacitated such that informed consent cannot be obtained; 
29. Inability or unwillingness to complete daily hot flash diary and study questionnaires 
appropriately; and  
30. Participation in another investigational trial within the past 30 days. 
 
 

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6 
STUDY DRUG(S) AND CONCOMITANT MEDICATIONS 
6.1 
Description and Handling of Study Drug 
The term study drug refers to G-CSF and placebo. 
6.1.1 
Study Drug 
G-CSF will be obtained as Neupogen® (filgrastim) and is a sterile‚ clear‚ colorless‚ 
preservative-free liquid for parenteral administration.  
 
Clear, sterile physiological, preservative free, isotonic saline will be used for the placebo. 
 
Additional information regarding G-CSF can be found in the Investigator’s Brochure. 
6.1.2 
Packaging and Labeling 
G-CSF will be used as packaged in individual 1.0 mL vials containing 300 mcg of G-CSF 
(labelled as Neupogen® (filgrastim) [16]. Sterile physiological, preservative free, isotonic 
saline will be used from individual vials for placebo.   
6.1.3 
Storage and Handling 
Vials of study drug should be stored in a refrigerator at a temperature between 2° and 8°C 
(36° to 46°F). Avoid shaking. Prior to injection‚ study drug may be allowed to reach room 
temperature for a maximum of 24 hours. Any vial or prefilled syringe left at room 
temperature for greater than 24 hours should not be used. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration‚ whenever 
solution and container permit; if particulates or discoloration are observed‚ the container 
should not be used [16].  
Study drug should be stored in a secure, limited-access storage area accessible only to 
designated study personnel. 
Saline should be stored in a refrigerator at a temperature between 2° and 8°C (36° to 46°F) in 
order to follow the exact same process for storage and handling of G-CSF. 
6.1.4 
Procedure 
Additional details regarding the procedures to prepare syringes will be provided in a separate 
Pharmacy study manual. 
Subjects will be assigned to double-blind treatment by the randomization number in 
sequential order.  

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Subjects, investigators, site staff with contact with subjects or subject records will remain 
blinded to study treatment during the study.  
6.1.5 
Breaking the Blind 
An unblinded designee will be responsible for maintaining the blind throughout the study. If 
a subject becomes seriously ill or pregnant during the study, the blind will be broken only if 
knowledge of the administered study drug will affect treatment options available to the 
subject. Every attempt will be made to maintain the blind throughout the study and the blind 
can only be broken with the written consent of the MenoGeniX medical/safety director. 
Instructions for breaking the blind in the event of an emergency can be found in the study 
manual provided to each site. 
6.2 
Preparation and Administration of Study Drug 
Study drug will be administered in a double-blind fashion for the study as a SC injection on 
an outpatient basis.  
All unused study materials are to be returned to MenoGeniX or its designee after the clinical 
phase of the study has been completed. 
6.2.1 
Adverse Events Associated with Drug Administration 
G-CSF is an FDA-approved drug with widespread human experience to date. See Table 1 for 
a summary of AEs associated with G-CSF (filgrastim) administration. For additional 
description of anticipated safety in single dose healthy volunteer studies, see Section 2.4. 
Additional safety data are summarized in the Investigator’s Brochure. The warnings 
and precautions regarding the clinical use of G-CSF apply to the setting of 
chemotherapy-induced, congenital or idiopathic severe neutropenia and involve 
multiple daily injections over extended periods of time. These events are much more 
serious than what is expected with a single SC dose repeated 28-days apart in healthy 
postmenopausal women which should be comparable to published healthy volunteer 
data, where serious safety events were not observed and where adverse events were 
generally mild [22,23,24,25], as also observed in the pilot study MNGX-101.  
 
Table 1: 
Common Side Effects Associated with Drug Administration [16] 
Common Side Effects Included in the Neupogen® Package Insert 
• 
Sensitivity at injection site 
• 
Risk of mild to moderate bone pain (normally seen with repeated dosing) 

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6.3 
Drug Accountability 
MenoGeniX requires that drug accountability logs be maintained. These logs must record 
quantities of study drug and quantity dispensed to subjects, including lot/batch number, date 
and time dispensed, subject identifier number, protocol number, dose, balance forward, 
expiry date, the initials of the person preparing the study drug syringes, and the person giving 
the injection should be recorded.  Used drug vials will be maintained on-site until end of 
study closeout, and will be labeled with subject initials, subject number and date and time 
dispensed. 
6.4 
Concomitant Medications/Dietary Supplements 
All concomitant medications and any dietary supplements will be recorded on the CRF. 
6.4.1 
Prohibited Concomitant Medications and Potential for Drug Interactions 
Drug interactions between G-CSF and other drugs have not been fully evaluated. Drugs 
which may potentiate the release of neutrophils‚ such as lithium and corticosteroids‚ should 
not be used while on study.  
Hormone replacement therapy or oral contraceptives, alternative or complementary 
medicines or herbs for menopausal symptoms, any SSRI, SNRI, or SERM, gabapentin, 
clonidine, megestrol acetate (Megace), and any anti-inflammatory biologics are prohibited 
while on study (see Appendix 2 for full list). 
6.4.1.1 
Investigational Drug Therapies 
Subjects must not receive any other investigational drugs, devices, or procedures during the 
study period. 
 
 

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7 
STUDY PROCEDURES 
The study procedures to be conducted for each subject enrolled in the study are presented in 
Appendix 1 and detailed in the text that follows.  
7.1 
Subject Enrollment and Study Drug Randomization 
Before recruitment of subjects into the study, written IRB approval of the protocol, informed 
consent, advertising materials, and any additional subject information must be obtained. A 
screening log will be maintained to record all subjects who sign the informed consent form 
(ICF). 
The principal investigator is responsible for verifying that the subject is eligible before study 
drug treatment. If any of the inclusion criteria are not met or any of the exclusion criteria are 
met, the subject should not be enrolled to receive study drug, however if the principal 
investigator would like to request a deviation for a subject, this must be approved by 
MenoGeniX. A site sequential screening number will be assigned to all subjects who sign an 
informed consent form. At Baseline, a unique subject number will be assigned to each 
enrolled subject. Once a subject is enrolled in the study, she will only be identified by her 
initials and the assigned subject number. 
Randomization will be performed by a MenoGeniX unblinded designee. Randomization lists 
will be provided to each study site (electronically or paper). Subjects who have been 
confirmed for all eligibility criteria at Baseline will be randomized to active treatment with 
300 mcg G-CSF or placebo in a 1:1 ratio.  
Subjects must complete 14 days of run-in, then be treated at the Baseline Visit within 1 
day after the run-in period. If there are more than 21 days between Screening and 
Baseline visits, labs will be repeated and reviewed prior to Randomization.  
7.2 
Study Procedures and Assessments 
The Study Procedures Table is presented in Appendix 1. 
Participants who meet screening eligibility requirements will participate in the study over 
approximately 12 weeks. The Screening visit will occur after the subject has been telephone 
screened by the research site staff. Some items during the screening visit may be performed 
via Telehealth/Zoom when appropriate. After the subjects complete the first 7 days of the 14-
day run-in period of hot flash diary collection, the site staff will call the subject to review and 
record the daily hot flash frequency and severity. If a subject appears to qualify with at least 7 
moderate to severe hot flashes per day on average, (equivalent to 49 moderate to severe hot 

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flashes per week), the subject will be scheduled for the Baseline visit, which should be 
scheduled after the completion of the 14-day run-in period, and the subject will be instructed 
to continue recording their hot flashes on the diary. Study drug administration will occur at 
the Baseline visit. The final study visit will occur at the end of 12 weeks.  
Subjects must complete the Screening 14-day run-in period and daily diary entry of hot flash 
frequency and severity, to confirm eligibility prior to Baseline. 
Procedures/assessments must be completed in the order as described below: 
Visit 1 (Screening visit): 
• Sign informed consent (may be performed via Telehealth/Zoom when appropriate); 
• Screening number assigned (site sequential); 
• Demographics, medical and medication/dietary supplement history (including 
smoking and alcohol history) and medical record documentation of a pelvic exam and 
pap smear within 2 years is required (may be performed via Telehealth/Zoom when 
appropriate); 
• General physical exam (including vitals, temperature, weight, and height); 
• Hormone status/reproductive & hot flash history (may be performed via 
Telehealth/Zoom when appropriate);  
• Blood and serum samples will be collected for non-fasting clinical chemistry, HbA1c, 
CBC with differential, TSH, FSH, and cytokines (time recorded); and 
• Subjects are instructed on hot flash diary completion. Subject instructed to complete 
diary twice a day at same time (AM and PM) and given hot flash diary to complete 
for the next week(s).   
Coordinator-to-Subject phone call (on day 7 of the 14-day run-in period [day -8]): 
• Subject is called to review and record the daily hot flash frequency and severity for 
the last 7 days. Subject must have at least 7 moderate to severe hot flashes per day on 
average, or 49 moderate to severe hot flashes per week to continue. If the minimum 
number of hot flashes is confirmed, the Baseline visit will be scheduled to occur after 
the 14-day run-in. 
• Subject will be instructed to continue recording daily hot flashes on diary. 
 

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Visit 2 (Baseline visit – Day 0): 
• Hot flash diary collected, reviewed and confirmed for eligibility requirements (must 
have minimum of 14 full days recorded). This part of the visit may take place via 
Telehealth/Zoom when appropriate; 
• The HFRDIS, ISI, MENQOL, FSS, and AIMS will be completed by subject using 
RedCap prior to the in-person segment of this visit (paper questionnaires will be 
available to subjects as back up); 
• Vitals, temperature, and weight will be obtained;  
• A urine sample will be collected, and pregnancy test performed to confirm negative 
pregnancy test prior to study drug injection; 
• Concomitant medications and medical history update is reviewed/documented (may 
be performed via Telehealth/Zoom when appropriate); 
• Blood and serum samples will be obtained for CBC with differential, hormones and 
cytokines (time recorded). Lab results are not required prior to study drug injection; 
• Subject number assigned; 
• After all eligibility requirements are confirmed, subject will be given injection of 
study drug (G-CSF or placebo) per randomization list; 
• Subject instructed to complete diary twice a day at same time (AM and PM) and 
given hot flash diary to complete for the next three weeks; and 
• Next visit is scheduled. 
Visit 3 (Day 1): 
• Hot flash diary reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam); 
• Blood and serum samples will be obtained for non-fasting clinical chemistry, CBC 
with differential, hormones and cytokines (time recorded); 
• Subject instructed to continue completing diary twice a day at same time (AM and 
PM); and 
• Next visit is scheduled. 

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Coordinator-to-Subject phone call (end of weeks 1 and 2): 
• Subject is called as follow-up between clinic visits to inquire if any adverse events 
have occurred (will be documented), and as reminder to complete hot flash diary at 
same time twice a day (AM and PM).   
Visit 4 (Day 21): 
• Hot flash diary collected and reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam); 
• Blood and serum samples will be obtained for non-fasting clinical chemistry, CBC 
with differential, hormones and cytokines (time recorded); 
• Subject instructed to complete diary twice a day at same time (AM and PM) and 
given hot flash diary to complete for the next week; and 
• Next visit is scheduled. 
Visit 5 (Day 28): 
• The HFRDIS, ISI, MENQOL, AIMS, and FSS are completed by subject, using 
RedCap, prior to the in-person segment of this visit (paper questionnaires will be 
available to subjects as back up); 
• Vitals, temperature, and weight will be obtained;  
• A urine sample will be collected and pregnancy test performed to confirm negative 
pregnancy test prior to study drug injection; 
• Hot flash diary collected and reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam); 
• Blood and serum samples will be obtained for non-fasting clinical chemistry, CBC 
with differential, hormones and cytokines (time recorded); 
• Subject will be given injection of study drug (G-CSF or placebo) per randomization 
list; 

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• Subject instructed to complete diary twice a day at same time (AM and PM) and 
given hot flash diary to complete for the next three weeks; and 
• Next visit is scheduled. 
Visit 6 (Day 29): 
• Hot flash diary reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam); 
• Blood and serum samples will be obtained for non-fasting clinical chemistry, CBC 
with differential, hormones and cytokines (time recorded); 
• Subject instructed to continue completing diary twice a day at same time (AM and 
PM); and 
• Next visit is scheduled. 
Coordinator-to-Subject phone call: (end of weeks 5, and 6): 
• Subject is called as follow-up between clinic visits to inquire if any adverse events 
have occurred (will be documented), and as reminder to complete hot flash diary at 
same time twice a day (AM and PM).   
Visit 7 (Day 49): 
• Hot flash diary collected and reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam); 
• Blood and serum samples will be obtained for non-fasting clinical chemistry, CBC 
with differential, hormones and cytokines (time recorded); 
• Subject instructed to complete diary twice a day at same time (AM and PM) and 
given hot flash diary to complete for the next week; and 
• Next visit is scheduled. 
 
 

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Visit 8 (Day 56): 
• The HFRDIS, ISI, MENQOL, AIMS, and FSS are completed by subject, using 
RedCap, prior to the in-person segment of this visit (paper questionnaires will be 
available to subjects as back up); 
• Vitals, temperature, and weight will be obtained;  
• A urine sample will be collected, and pregnancy test performed to confirm negative 
pregnancy test prior to study drug injection; 
• Hot flash diary collected and reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam);  
• Blood and serum samples will be obtained for CBC with differential, hormones and 
cytokines (time recorded); 
• Subject will be given injection of study drug (G-CSF or placebo) per randomization 
list; 
• Subject instructed to complete diary twice a day at same time (AM and PM) and 
given hot flash diary to complete for the next four weeks; and 
• Next visit is scheduled. 
Visit 9 (Day 57): 
• Hot flash diary reviewed for completion; 
• AEs and concomitant medications/dietary supplements are reviewed and documented 
and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam);  
• Blood and serum samples will be obtained for non-fasting clinical chemistry, CBC 
with differential, hormones and cytokines (time recorded); 
• Subject instructed to continue completing diary twice a day at same time (AM and 
PM); and 
• Next visit is scheduled. 
 

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Coordinator-to-Subject phone call: (end of weeks 9, 10 and 11): 
• Subject is called as follow-up between clinic visits to inquire if any adverse events 
have occurred (will be documented), and as reminder to complete hot flash diary at 
same time twice a day (AM and PM).   
Visit 10 (Final – Day 84): 
• The HFRDIS, ISI, MENQOL, AIMS, and FSS are completed by subject, using 
RedCap, prior to the in-person segment of this visit (paper questionnaires will be 
available to subjects as back up); 
• General physical exam (including vitals, temperature, and weight); 
• A urine sample will be collected, and pregnancy test performed to confirm negative 
pregnancy test; 
• Hot flash diary collected and reviewed for completion; 
• Adverse events and concomitant medications/dietary supplements are reviewed and 
documented and physical exam as necessary based on history (may be performed via 
Telehealth/Zoom when appropriate, with the exception of the physical exam); and 
• Blood and serum samples will be obtained for chemistry, CBC with differential, 
hormones and cytokines.   
Follow-up Coordinator-to-Subject phone call: (30-days post Final Visit): 
• Subject is contacted approximately 30-days following last clinic visit to inquire if any 
adverse events occurred (will be documented), and to inquire about subject status.   
7.2.1 
Clinical Laboratory Tests 
Additional laboratory handling instructions can be found in the Laboratory procedures study 
manual provided to each site. Date and time will be recorded for all laboratory collections. 
Local laboratory results (chemistry, HbA1c, and TSH, BUT NOT CBC with differential) 
should be reviewed promptly by the investigator and will be transcribed into the electronic 
Case Report Forms (eCRFs) for data collection. 
CBC with differential results at Days 1, 21, 28, 29, 49, 56, 57, and 84 will not be returned to 
the Investigator in order to avoid treatment unblinding and will be reviewed by the 
Medical/Safety Monitor. If of significant clinical concern, the results will be discussed with 
the Investigator.   

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A copy of the local laboratory normal reference ranges and laboratory certifications should 
be provided to MenoGeniX prior to the initiation of the study. MenoGeniX should be notified 
of any subsequent revisions to the normal ranges.  
Chemistry (including sodium, potassium, calcium, ALT, AST, bilirubin, creatinine, BUN, 
alkaline phosphatase, and albumin will be performed at Screening in order to assess 
eligibility for the study and repeated at every visit. TSH, FSH, and HbA1c will be performed 
at Screening to assess for eligibility. 
CBC with differential (including RBC, WBC, platelets, hemoglobin, hematocrit, RDW, 
MCV, MCH, MCHC, neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
neutrophils [absolute], lymphocytes [absolute], monocytes [absolute], eosinophils [absolute], 
basophils [absolute]) will be performed at Screening in order to assess eligibility for the study 
and repeated at every study visit. 
Hormone and cytokine levels will be collected at Baseline (additional baseline cytokine 
collection at the Screening visit) and repeated at every visit. The circulating hormone levels 
to be assessed will include FSH, LH, TSH, DHEA, DHEAS, testosterone, and estradiol. The 
circulating cytokine levels to be assessed will include (but will not be limited to) IL-1, IL-6, 
IL-8, and TNF-alpha. The samples for both the hormones and cytokines will be collected, 
processed, aliquoted, and frozen at -70 degrees Celsius or lower and will be sent to 
MenoGeniX at the end of the study for batch analysis in 2 separate shipments. If a -70 
degrees or lower Celsius freezer is not available at the site, samples will be couriered the 
same day to a facility with a -70 degrees Celsius freezer is available. Please refer to the 
Laboratory procedures study manual for additional details.  
7.2.2 
Daily Hot Flash Diary 
Subjects will be instructed to complete the hot flash diary twice-a-day at the same time for 
the duration of the study. A time in the morning and evening should be scheduled with the 
subject to record hot flash frequency and severity. A new diary will be given at each visit and 
collected at the following visit. If, upon review of the hot flash diary, it is noted the subject 
has not been compliant with completing the diary, this should be discussed with the subject 
during the visit. If the subject is noncompliant for at least a total of two weeks, consideration 
should be made regarding discontinuing the subject from the study following discussion 
between the Investigator and MenoGeniX.  
The coordinator will discuss with the subject if an additional reminder should be set-up (such 
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Data from the hot flash diary will be transcribed on the CRFs for data collection and the diary 
filed as a source document.   
7.2.3 
Questionnaires 
Hot Flash Related Daily Interference Scale (HFRDIS) (Appendix 3), Insomnia Severity 
Index (ISI) (Appendix 4), Menopause-specific Quality of Life Questionnaire (MENQOL) 
(Appendix 5), Fatigue Severity Scale (FSS) (Appendix 6) and Arthritis Impact Measurement 
Scale (AIMS) (Appendix 7) will be completed at Baseline and repeated at Visit 5 (Day 28), 
Visit 8 (Day 56) and Visit 10 (Day 84/Final Visit).  
Questionnaires should be completed by the subject at the beginning of the visit before 
collection of the hot flash diary and before any other procedure or assessment is completed. 
7.2.4 
Coordinator-to-Subject Phone Calls   
Coordinator-to-Subject phone call will occur at the end of every week the subject is not seen 
in clinic (Weeks 1, 2, 5, 6, 9, 10, and 11) and will be documented.  A time should be 
scheduled for the coordinator to call the subject. The subject will be asked how they are 
doing and asked about compliance in completing the hot flash diary at same time twice-a-day 
(AM and PM). If any adverse events are relayed by the subject, these should be recorded by 
the coordinator. 
If the subject cannot be reached at the scheduled time, 2 additional documented attempts 
should be made by the coordinator to reach the subject each week.  
7.2.5 
Final Coordinator-to-Subject Phone Call 
Subject is contacted approximately 30 days following last clinic visit to inquire if any adverse 
events occurred (will be documented), and to inquire about subject status.   
7.3 
Criteria for Study Discontinuation 
Criteria for study discontinuation will include: 
• Pregnancy, medical or ethical reasons; 
• Total of at least two weeks of noncompliance with hot flash diary entry, following 
discussion between the Investigator and MenoGeniX; 
• Subject request (excluding adverse events); 
• Regulatory reasons; and/or 
• Administrative reasons  
 

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8 
ADVERSE EVENTS 
8.1 
Safety Assessment 
Assessments will consist of monitoring and recording physical exams, AEs/SAEs, clinical 
chemistry, and CBC. The study-specific procedures and assessments are described in Section 
7 and summarized in the Study Procedures Table (Appendix 1). All subjects who have 
received an injection of study drug will be evaluated for safety of the study drug. 
8.1.1 
Clinical Laboratory Abnormalities 
It is the responsibility of the Investigator to assess the clinical significance of all abnormal 
values as defined by the list of normal values from the local laboratory. All clinically 
significant laboratory values should be recorded as AEs if they meet the definition in 
Section 8.2. 
CBC with differential results Days 1, 21, 28, 29, 49, 56, 57, and 84, will be reviewed by the 
Medical/Safety Monitor and results that may be clinically significant will be discussed with 
the Investigator. 
8.2 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence, including the exacerbation of a 
pre-existing condition, in a subject or clinical investigation subject administered a 
pharmaceutical product. This does not necessarily have a causal relationship with this 
treatment. 
8.3 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is any experience that suggests a significant hazard, 
contraindication, side effect, or precaution. This includes any experience that: 
• Results in death; 
• Is acutely life-threatening; 
• Requires inpatient hospitalization or prolongs the existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of ability to 
conduct normal life functions; 
• Is a congenital anomaly/birth defect; or 
• Requires medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 

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convulsions that do not result in in-subject hospitalization, or the development of 
drug dependency or drug abuse. This definition includes intercurrent illness or 
injuries, exacerbation of pre-existing conditions and adverse events occurring as a 
result of drug withdrawal, abuse or overdose.  
If a SAE is reported from the study, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e., G-CSF or placebo according to the study design. 
If the SAE meets the regulatory criteria of being related to the drug, and is not listed in the 
Investigator’s Brochure, then it must be reported to the manufacturer of the drug under the 
appropriate regulatory statutes of post-marketing safety reporting. 
8.4 
Adverse Event Reporting Period 
Any AE (i.e., a new event or an exacerbation of a pre-existing condition) that occurs after the 
subject is randomized and receives study drug treatment must be recorded as an AE on the 
appropriate page(s) of the CRF. Any SAE that occurs more than 30 days after the last study 
visit should be reported if considered related to study drug. The evaluation of an AE should 
continue until the adverse event resolves, or until the Investigator or Sponsor determines the 
subject’s condition is stable. 
8.5 
Adverse Event Assessment and Documentation 
A consistent methodology for eliciting AEs should be adopted. Examples of nondirective 
questions include: “How have you felt since your last clinical visit?” or “Have you had any 
new or changed health problems since you were last here?” Clinically significant laboratory 
abnormalities should be reported as AEs. 
All AEs will be assessed by the Investigator and recorded on the appropriate CRF page, 
including the dates of onset and resolution, severity, relationship to study drug, seriousness, 
and the action taken with the study drug. Any medication necessary for treatment of the 
serious adverse event must be recorded on the concomitant medication section of the 
subject’s CRF and, if applicable, on the Serious Adverse Event Report Form. 
Correct medical terminology/concepts should be used when recording AE terms. 
Abbreviations should be avoided. A diagnosis is preferred rather than individual signs and 
symptoms (e.g., record pneumonia rather than fever, cough, pulmonary infiltrate). An 
adverse event that meets serious criteria should be recorded both on the Adverse Event CRF 
and on the Serious Adverse Event Report Form. The Serious Adverse Event Report Form 
must be submitted to MenoGeniX within 24 hours of when the investigator becomes aware of 
the SAE (see Section 8.6). 

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The adjectives “severe” and “serious” are not synonymous. Serious is a regulatory definition 
(see Section 8.3), while severity describes the intensity of the adverse event. Severity should 
be recorded and graded according to the CTCAE, V5.0 (refer to the following website for the 
CTCAE manual or the CTCAE document): 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
The relationship to study drug therapy should be assessed using the following definitions: 
• Not Related: Evidence exists that the adverse event has an etiology other than the study 
drug (e.g., pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication). This includes events that are considered remotely or unlikely related to 
study drug. 
• Related: A temporal relationship exists between the event onset and administration of the 
study drug. It cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies. In case of cessation or reduction of the dose, the event 
abates or resolves and reappears upon re-challenge. It should be emphasized that 
ineffective study drug treatment should not be considered as causally related in the 
context of adverse event reporting. This includes events that are considered possibly, 
probably, or definitely related to study drug. 
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment. 
8.5.1 
Definition of Severity of Adverse Events to Study Drug 
All adverse events will be examined to determine severity. All AEs should be graded 
according to the Common Toxicity Criteria V5.0 (dated November 2017). In the case where 
an AE does not have a criterion, the categories are as follows: 
 
Mild: 
Awareness of sign, symptom, or event, but easily tolerated 
Moderate: 
Discomfort enough to cause interference with usual activity and 
may warrant intervention 
Severe: 
Incapacitating with inability to do usual activities or significantly 
affects clinical status, and warrants intervention 
Life-threatening: 
Immediate risk of death 

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8.6 
Serious Adverse Event Reporting Requirements 
MenoGeniX is required to evaluate and expedite reporting of SAEs to regulatory authorities; 
therefore, the appropriate parties, as specified in this section, must be notified immediately 
regarding the occurrence of any serious adverse event. 
All SAEs, regardless of relationship to study drug, must be reported to the Sponsor within 24 
hours of the Investigator’s knowledge. This should be done by faxing the completed SAE 
Form to the Sponsor at the number provided on the SAE Form. 
The procedure for reporting serious adverse events, regardless of causal relationship, is as 
follows: 
• Complete and sign the SAE Report Form. The form must contain sufficient information 
to enable medical assessment by MenoGeniX. 
• If it is felt that a SAE is not related to study drug therapy, then an alternative explanation 
should be provided on the SAE Report Form. 
• Fax the completed SAE Form to the Sponsor at the number provided on the SAE Form.  
• Copies of medical records including radiology reports, laboratory results, and autopsy 
reports may also be attached to the serious adverse event report as applicable. Please omit 
the subject’s name and medical record number from the documents to ensure anonymity. 
MenoGeniX may request additional information from the Investigator to ensure the timely 
completion of accurate safety reports. 
8.7 
Serious Adverse Event Report Distribution 
A SAE may qualify for reporting by MenoGeniX to regulatory authorities according to the 
statutes of post-marketing safety reporting and all Investigators actively participating in a 
clinical study of G-CSF if the SAE is attributable to the study drug and is 
unexpected/unlisted based upon safety information in the current Investigator’s Brochure. In 
this case, a formal notification describing the SAE and similar reports will be communicated 
by MenoGeniX.  
MenoGeniX will notify the Investigator and the Investigator must notify the IRB of SAEs in 
writing and in accordance with regulations and local institutional policy. 

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8.8 
Expected Adverse Events 
The MenoGeniX Investigator’s Brochure contains a complete description of the safety 
information for G-CSF. An expected adverse event is one that is described in the 
Investigator’s Brochure and is not different in severity. 
8.9 
Pregnancy 
While not expected to occur in this study’s population, pregnancies are not considered to be 
AEs or SAEs; however, pregnancies must be reported to MenoGeniX following the SAE 
timelines. Pregnancies will be followed through to outcome.  
Available data from published studies, including several observational studies of pregnancy 
outcomes in women exposed to filgrastim products and those who were unexposed, have not 
established an association with Neupogen® use during pregnancy and major birth defects, 
miscarriage, or adverse maternal or fetal outcomes.  Additional information is described in 
the Investigator’s Brochure and in the Neupogen® package insert.   
 

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9 
STATISTICAL METHODS 
The primary objective of this pilot study is to describe the effects of three single (repeated) 
subcutaneous injection of G-CSF on the frequency and severity of hot flashes in 
postmenopausal women.  
The secondary objectives of this pilot study are to assess additional measures of hot flash 
burden, circulating hormone and inflammatory cytokine concentrations, and safety. 
9.1 
Sample Size 
In total, 65 subjects will be enrolled in this study. Subjects will be stratified by natural 
menopause or surgical menopause groups, and randomized 1:1 to either 300 mcg G-CSF or 
placebo.  
The sample size of 65 subjects is based on clinical feasibility. This is a phase 1b study to 
determine feasibility of the treatment and the ability to conduct a larger powered study.   
9.2 
Study Endpoints 
9.2.1 
Safety 
Safety of three single subcutaneous injections of G-CSF at 28-day intervals in a 
postmenopausal healthy subpopulation; 
9.2.2 
Evaluation of Effect 
Changes from baseline throughout the entire 12 weeks will be evaluated in the:  
Primary Endpoints: 
• Safety and pharmacodynamics. 
o Pharmacodynamic Endpoints: Assessment of changes from baseline in 
circulating white blood cells, hormone and inflammatory cytokine 
concentrations. 
 
Secondary Endpoints: 
• Clinical endpoints 
The effect of repeated administration of G-CSF in the following indicators of vasomotor 
symptoms in women with naturally occurring or surgically induced menopause at weeks 
2, 4, 6, 8, 10 and 12 weeks post-administration: 
• Hot flashes – change from baseline in: 

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o Frequency of total daily hot flashes (mild + moderate + severe hot flashes) 
o Daily frequency of moderate + severe hot flashes 
o Daily composite hot flash severity score (1 x mild + 2 x moderate + 3 x severe 
hot flashes)  
o Hot flash severity score ((1 x mild + 2 x moderate + 3 x severe hot flashes)/total 
hot flashes) 
• Quality of life questionnaires - change from baseline in: 
o Hot Flash Related Daily Interference Scale (HFRDIS) 
o Fatigue Severity Scale (FSS) 
o Insomnia Severity Index (ISI) 
o Menopause-specific Quality of Life Questionnaire (MENQOL) 
o Arthritis Impact Measurement Scale (AIMS)  
o Frequency and severity of hot flashes. 
 
9.2.3 
Exploratory Analyses 
Changes from baseline throughout the entire 12 weeks and will be evaluated in the:  
Secondary Endpoints: 
• Circulating hormone levels as a result of three injections of G-CSF or placebo; 
and 
• Circulating pharmacodynamics and inflammatory cytokine levels as a result of 
three injections of G-CSF or placebo. 
9.3 
Data Analysis  
All analyses will be looked at as per protocol population and intent to treat population, as 
applicable, and will employ descriptive statistics (means, medians, etc.) and post-hoc 
hypothesis testing. 
This is an exploratory, pilot study intended to gather descriptive information on safety and 
effect, and no a priori assumptions are made regarding estimated treatment effects or 
statistical power. 
9.3.1 
Evaluation of Effect 
The frequency of hot flashes per day will be calculated for each week, providing that within a 
week at least 4 days’ worth of information were gathered. Missing data will be averaged from 
available weekly data. Descriptive statistics will be used to describe changes from baseline in 
average frequency and severity of hot flashes.  

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Descriptive statistical analyses will be performed to compare pre-treatment to all post-
treatment points using analysis of variance (ANOVA), with appropriate post hoc testing, to 
determine statistical significance of the observed effects. 
Primary Endpoints: 
Descriptive statistics will be used to analyze changes from baseline throughout the entire 12 
weeks in frequency and severity of hot flashes. The frequency and severity of hot flashes will 
be examined separately by comparing the Baseline hot flash frequency and severity per 
Baseline week to the frequency throughout the entire 12 weeks.  
Secondary Endpoints: 
Descriptive statistics will be used to analyze changes from baseline throughout the entire 12 
weeks in Hot Flash Related Daily Interference Scale (HFRDIS); Insomnia Severity Index 
(ISI); Menopause Specific Quality of Life Questionnaire (MENQOL); Fatigue Severity Scale 
(FSS), and Arthritis Impact Measurement Scale (AIMS). The HFRDIS, ISI, MENQOL, FSS, 
and AIMS will also be scored at all relevant study weeks (Baseline, Days 28, 56, and 84).  
9.3.2 
Exploratory Analysis 
9.3.2.1 
Circulating Hormone and Proinflammatory Cytokine Levels 
Descriptive exploratory analyses will be performed to determine whether or not G-CSF or 
placebo administration affects endogenous circulating hormone levels (FSH, LH, TSH, 
DHEA, DHEAS, testosterone, and estradiol) and proinflammatory cytokine effects (including 
but not limited to IL-1, IL-6, IL-8, and TNF-alpha) at every visit. ANOVA will be performed 
as described above. 
9.3.3 
Safety 
Safety will be analyzed as intent to treat population. All subjects who receive the injection of 
G-CSF or placebo will be considered evaluable for all safety analyses.  
Descriptive statistics will be used to summarize safety data, and summary tables for all AEs 
will be generated. Additional summary tables may be generated for the following population 
subsets: subjects with related AEs, subjects with SAEs, subjects with related SAEs, subject 
deaths, and subjects who discontinue due to AEs.  
9.3.3.1 
Adverse Events 
All incidences of AEs will be looked at including seriousness, deaths, and discontinuation 
due to adverse events. Severity, Investigator-attributed relationship to study drug, duration, 

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and outcome of the events will also be recorded. These AEs will be coded by body system. 
The number and percent of each event will be calculated and summarized by body system. 
9.3.3.2 
Laboratory Data 
Descriptive statistics will be used to summarize lab data. Chemistry and CBC data will be 
displayed in tabular form, with values outside of normal ranges noted.  
 
 
 

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10 
STUDY CONDUCT 
10.1 
Adherence to the Protocol 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
Deviations from the protocol should be minimized. In the case of significant deviations from 
the protocol, the sponsor must be notified immediately. In the case of major deviation, the 
sponsor and the investigator will determine whether the IRBs and regulatory authorities, 
should be notified in accordance with local requirements. 
Changes to the protocol may be made only when a written protocol amendment provided by 
the Sponsor has been signed by the Investigator and approved by the IRB and applicable 
regulatory agencies in accordance with local requirements. 
10.2 
Recording and Collecting of Data 
10.2.1 
Case Report Forms 
MenoGeniX will provide CRFs, either in a paper or electronic format, for the recording and 
collecting of data. All CRFs, including any corrections, will be completed by site staff in a 
manner appropriate to the CRF format. The investigator or site designee must complete CRFs 
within a reasonable time period after data collection. 
The Investigator will sign and date all CRF signature modules to indicate that, to his/her 
knowledge, the data contained in the CRF are complete and accurate. 
Once the CRFs have been collected, queries or site notifications will be generated and 
submitted to the sites for completion. The Investigator will be responsible for assuring that all 
corrections have been addressed and have been acknowledged by the Investigator’s or site 
designee’s signature and date on each query or site notification form. 
10.2.2 
Study Files and Subject Source Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents include Investigators’ Study Files and original subject clinical source documents 
generated at the study site. The term “original” means the first recording of the data. 
The Investigator will ensure the Study Files are maintained, including the CRFs and query 
forms, protocol/amendments, IRB and regulatory approvals with associated correspondence, 

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informed consents, study drug records, staff curriculum vitae, all correspondence, and other 
appropriate documents. 
Subject clinical source documents may include, but are not limited to, subject hospital/clinic 
records, physicians’ and nurses’ notes, appointment books, diaries, questionnaires, laboratory 
reports. The Investigator must ensure that all original source documents are available to 
support monitoring activities. 
10.3 
Monitoring 
The Sponsor of this study is responsible for ensuring the proper conduct of the study with 
regard to protocol adherence and validity of data recorded in the CRFs. The Sponsor will 
oversee monitoring of the study by a CRA. The CRA is responsible for reviewing the CRFs 
at regular intervals throughout the study, verifying adherence to the protocol, ensuring 
completeness, consistency, and accuracy of the data, and reviewing study files and drug 
accountability (see Section 10.3.1). The original medical records and laboratory results (with 
the exception of the blinded CBC results) will be reviewed as part of source document 
verification to ensure validity of the data. The Investigator’s responsibility is to ensure that 
any issues detected in the course of a monitoring visit are resolved. When the CRF pages are 
completed and signed by the Investigator, they will be collected by the CRAs as applicable. 
10.3.1 
Drug Accountability 
As outlined in Section 6.1, the Investigator is responsible for ensuring adequate 
accountability of all used and unused study drug. All drug supplies and associated 
documentation will be reviewed and verified by the CRA. Unused material cannot be 
disposed of until approval is obtained from the CRA. The study site is responsible for the 
disposal and/or destruction of all unused study drug supplies, according to the site’s standard 
operating procedures. If the site cannot dispose of these materials, arrangements should be 
made between the site and the Sponsor or its representative for destruction or return of the 
unused study drug supplies. 
10.4 
Retention of Records 
All clinical study documents must be retained by the Investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., US, Europe, or Japan) and 
until there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after 
the investigation is discontinued and regulatory authorities have been notified. Investigators 

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may need to retain documents longer if required by applicable regulatory requirements or if 
requested by the Sponsor. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the Investigator and the 
Sponsor to store these documents in sealed containers in an off-site storage location so they 
can be retrieved by the Investigator in case of a regulatory inspection. Where source 
documents are required for the continued care of the subject, appropriate copies should be 
made for off-site storage. 
10.5 
Inspection 
Good Clinical Practice (GCP) regulations require independent inspection of clinical program 
activities. Such inspections may be performed at any time before, during, and/or after the 
study. The Investigator and study staff are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection 
at any time by the Sponsor, its designees, and/or regulatory agencies. In signing this protocol, 
the Investigator understands and agrees to give access to the necessary documentation and 
files. 
10.6 
Legal and Ethical Requirements 
10.6.1 
Good Clinical Practice 
The Investigator will ensure that this study is conducted in full compliance with GCP, which 
includes ICH GCP guidelines, applicable GCP regulations, and with any other applicable 
laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. 
10.6.2 
Institutional Review Board Approval 
The Investigator must submit this protocol, the informed consent form(s), and any 
accompanying material that will be provided to the subject (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) to the IRB, 
if unable to use the central IRB. Approval from the board/committee must be obtained before 
starting the study and documented in writing to the Investigator specifying the protocol 
number, protocol version, documents reviewed, and date on which the committee met and 
granted the approval. Written evidence of the approval must be made available to the 

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Sponsor. Any modifications made to the protocol after receipt of IRB approval must also be 
submitted to the board/committee for approval prior to implementation. 
Appropriate reports on the progress of the study will be made to the IRB in accordance with 
applicable regulations, institutional policy, and in agreement with policies established by the 
Sponsor. 
10.6.3 
Informed Consent 
The Investigator will submit the informed consent to the Sponsor for approval prior to 
submitting to the IRB. The Investigator is responsible for obtaining written, informed 
consent(s) from each subject interested in participating in this study prior to conducting any 
study-related procedures. Written informed consent should be obtained after adequate, 
thorough, and clear explanation of the aims, methods, objectives, potential risks, and benefits 
of the study, as well as any use of the subject’s genetic information from the study. The 
Investigator must use the most current IRB-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject and the person obtaining consent. The investigational site must retain the original 
signed consent and provide a copy to the subject. Documentation of the consent process 
should be documented in the subject’s medical record. 
Significant new safety information received by the Investigator should be provided to current 
and future study subjects at the first available opportunity. 
10.6.4 
Study Termination 
The Sponsor, the Investigator, and/or the regulatory authorities reserve the right to terminate 
the study at any time. Should termination be necessary, all parties will formulate and 
coordinate termination procedures. In terminating the study, the Sponsor and the Investigator 
will ensure that subjects’ safety and rights are carefully protected. 
10.6.5 
Regulatory Approval 
The Sponsor will determine the appropriate local, national, and/or regional regulatory 
approval(s) that need to be obtained in order to conduct this study. 
10.7 
Compensation, Insurance, and Indemnity 
The Sponsor will compensate the study center for providing care for the acute treatment of 
injury to a subject, which, in the judgment of the Investigator and the Sponsor, occurs 
directly as a result of the proper use of the study drug or procedures performed in accordance 
with the protocol, so long as (i) the injury was not a foreseeable side effect or attributable to 

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the negligence or willful misconduct of the Investigator or the study center or its personnel or 
attributable to the pre-existing abnormal medical condition or underlying disease, or (ii) the 
expense is not covered by the subject’s insurance. The subject’s right at law to claim 
compensation for injury where negligence can be proven is not affected. 
The Sponsor and the study center shall both maintain professional liability and other 
insurance reasonably necessary to insure themselves against any losses connected directly or 
indirectly with the study. The Sponsor will provide evidence of such coverage to the study 
center upon request. Issues of indemnity may be the subject of a separate document. 
10.8 
Disclosure of Information 
Information concerning G-CSF, the protocol, the study information, patent applications, and 
processes, scientific data, or other pertinent information is confidential and remains the 
property of MenoGeniX. The Investigator may use this information for the purpose of the 
study only. 
MenoGeniX will use information developed in this clinical study in connection with the 
development of G-CSF and, therefore, may disclose it as required to other clinical 
Investigators participating in this study and to regulatory agencies. In order to allow the use 
of the information derived from this clinical study, the Investigator understands that he/she 
has an obligation to provide all data produced during this study to MenoGeniX. 
MenoGeniX considers that clinical data (complete or incomplete) constitute sensitive 
information and MenoGeniX must fulfill its board directed obligations. Consequently, 
MenoGeniX requires that verbal or written discussion of results prior to study completion 
and full reporting should only be undertaken with MenoGeniX’s written consent. 
10.9 
Confidentiality and Data Protection 
Individual subject medical information obtained as a result of this study is considered 
confidential. The Investigator and the study center will adhere to all applicable laws relating 
to the protection of subject information. To assure that subject confidentiality is maintained, 
subject data will be identified by a study-assigned number and initials only. 
All MenoGeniX personnel will handle subject data in a confidential manner in accordance 
with applicable regulations governing clinical research. Subject records will be inspected 
only in connection with this research project. Information generated as a result of a subject’s 
participation in this study may be disclosed to third parties for research and regulatory 
purposes in any country as determined by MenoGeniX. However, subjects will not be 

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individually identified but will be referred to by the study-assigned number and the subject’s 
initials. 
10.10 
Study Report and Publications 
The Coordinating Investigator will have the responsibility to review the final study results to 
confirm to the best of his/her knowledge it accurately describes the conduct and results of the 
study. A Coordinating Investigator will be selected from the participating Investigators by 
MenoGeniX prior to database lock. 
After conclusion of the study, investigators in this study may make oral presentations of 
study results or publish such results in scientific journals or other scholarly media without 
prior written approval from MenoGeniX, only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of MenoGeniX in an abstract, manuscript, or presentation forum; 
• The investigator has complied with all requests from MenoGeniX to delete any references 
to its confidential information (other than study results); and 
• The study has been completed at all study sites for at least 2 years. 
The investigator may submit to MenoGeniX any proposed publication or presentation along 
with information about the scientific journal or presentation forum at least 90 days prior to 
submission of the publication or presentation (6 weeks for abstracts). The investigator will 
comply with requests from MenoGeniX to delete references to its confidential information 
(other than the study results) in any paper or presentation and agrees to withhold publication 
or presentation for an additional 120 days in order to obtain patent protection if deemed 
necessary. 
No such communication, presentation, or publication will include MenoGeniX’s confidential 
information.

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11 
REFERENCES 
 
1  Guthrie JR, Dennerstein L, Taffe JR, Donnelly V. Health care-seeking for menopausal 
problems. Climacteric 2003;6:112-7. 
2  Hendrix SL. Bilateral oophorectomy and premature menopause. Am J Med 2005;118:Suppl 
12B:131-5. 
3  Loprinzi CL, Barton DL, Sloan JA, et al. Mayo Clinic and North Central Cancer Treatment 
Group hot flash studies: a 20-year experience. Menopause 2008;15:655-60. 
4  Barnabei VM, Grady D, Stovall DW, et al. Menopausal symptoms in older women and the 
effects of treatment with hormone therapy. Obstet Gynecol 2002;100:1209-18. 
5  Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of 
estrogen plus progestin. JAMA 2005;294:183-93. 
6  Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in 
postmenopausal women with hysterectomy: the Women's Health Initiative randomized 
controlled trial. JAMA 2004;291:1701-12. 
7  Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus 
progestin in healthy postmenopausal women: principal results From the Women's Health 
Initiative randomized controlled trial. JAMA 2002;288:321-33. 
8  Grady D. Management of menopausal symptoms. N. Engl. J. Med. 2006; 355:2338-47. 
9  Multiple A. Management of menopausal symptoms. Am J Med 2005;118. 
10 Sicat BL and Brokaw DK. Nonhormonal Alternatives for the Treatment of Hot Flashes. 
Pharmacotherapy 2004;24:79-93. 
11 Pachman DR, Jones JM and Loprinzi C. Management of Menopause-Associated 
Vasomotor Symptoms: Current Treatment Options, Challenges and Future Directions. Int. 
J. Women’s Hlth. 2010;2:123-35. 
12 Advani SH, Achreckar S, Thomas D, Krishnankutty B. Granulocyte colony-stimulating 
factor (filgrastim) in chemotherapy-induced febrile neutropenia. Indian J Med Paediatr 
Oncol 2010;31:79-82 
13 Metcalf D. The CSFs and Cancer. Nat Rev Cancer 2010;10:425-434.  
 

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14 Advani SH, Achreckar S, Thomas D, Krishnankutty B. Granulocyte colony-stimulating 
factor (filgrastim) in chemotherapy-induced febrile neutropenia. Indian J Med Paediatr 
Oncol 2010;31:79-82. 
15 Pulsipher MA, Chitphakdithai P, Miller JP, et al. Adverse events among 2408 unrelated 
donors of peripheral blood stem cells: results of a prospective trial from the National 
Marrow Donor Program. Blood 2009;113:3604-11. 
16 Neupogen [package insert]. Amgen Inc.,Thousand Oaks, CA; June 2018.  
http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf. Accessed 
September 21, 2020. 
17 Lyman GH, Kuderer NM. Filgrastim in patients with neutropenia: potential effects on 
quality of life. Drugs 2002;62 Suppl 1:65-78. 
18 Chow I, Lemos EV, Einarson TR. Management and prevention of diabetic foot ulcers and 
infections: a health economic review. Pharmacoeconomics 2008;26:1019-35. 
19 Gertz MA. Current status of stem cell mobilization. Br J Haematol 2010;150:647-62. 
20 Divani AA, Hussain MS, Magal E, Heary RF, Qureshi AI. The use of stem cells' 
hematopoietic stimulating factors therapy following spinal cord injury. Ann Biomed Eng 
2007;35:1647-56. 
21 Scarpellini F, Sbracia M. 2009. Use of granulocyte colony-stimulating factor for the 
treatment of unexplained recurrent miscarriage: a randomized controlled trial. Human 
Reprod. 24:2703-2708. 
22 U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. 
Filgrastim (Neupogen) NDA 103353/000 approval letter, February 20, 1991. Retrieved 
January 1, 2013, from: 
http://www.accessdata.fda.gov/drugsatfda_docs/bla/pre96/103353Orig1s000.pdf 
23 Varki R, Pequignot E, Leavitt M, Ferber A, Kraft W. A Glycosylated Recombinant Human 
Granulocyte Colony Stimulating Factor Produced in a Novel Protein Production System 
(AVI-014) in Healthy Subjects: a First-in Human, Single Dose, Controlled Study. BMC 
Clinical Pharmacology 2009; 9:2.  
24 Waller CF, Bronchud M, Maiar S, Challand R. Pharmacokinetics Profiles of a Biosimilar 
Filgrastim and Amgen Filgrastim: Results from a Randomized, Phase 1 Trial. Ann 
Hematol 2010; 89:927-933.  
 

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25 Gascon P, Fuhr U, Sorgel F, Kinzig-Schippers M Makhson A, Balser S, Einmahl S, 
Munzberg M. Development of a New G-CSF Product Based on Biosimilarity Assessment. 
Annals of Oncology 2009;21:1419-1429.  
26 Freeman, EW et al. Efficacy of escitalopram for hot flashes in healthy menopausal women: 
A randomized controlled trial. JAMA 2011;19:267-274. 
27 Newton, KM et al. Treatment of vasomotor symptoms of menopause with black cohash, 
multibotanicals, soy, hormone therapy or placebo. A randomized trial. Ann. Intern. Med. 
2006;145:869-879. 
 

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12 
APPENDICES

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e Clinical chemistry includes (non-fasting): electrolytes, calcium, liver function tests (transaminase), bilirubin, creatinine, BUN, alkaline phosphatase, total protein, and albumin. 
HbA1c will only be checked at the Screening visit. 
f Negative urine pregnancy test must be confirmed prior to study drug injections. 
g CBC with differential includes: RBC, WBC, platelets, hemoglobin, hematocrit, RDW, MCV, MCH, MCHC, neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
neutrophils [absolute], lymphocytes [absolute], monocytes [absolute], eosinophils [absolute], basophils [absolute]). CBC with differential results at Days 1, 21, 28, 29, 49, 56, 
57, and 84, will not be returned to the Investigator in order to avoid treatment unblinding and will be reviewed by the Medical/Safety Monitor. If of significant clinical concern, 
the results will be discussed with the Investigator. 
h Hormones will include FSH, LH, TSH, DHEA, DHEAS, testosterone, and estradiol. Sample for FSH and TSH only at screening to confirm eligibility, remaining visit sample 
collections will be stored frozen (-70 degrees C) and batch shipped at end of study. 
i Cytokines will include (but will not be limited to) IL-1, IL-6, IL-8, and TNF-alpha. Two baseline serum samples will be collected, one at Screening and one at Baseline. 
Samples from all visits will be stored frozen (-70 degrees C) and batch shipped in two separate shipments at end of study. If a -70 degrees Celsius freezer is not available at the 
site, samples will be couriered the same day to a facility with a -70 degrees Celsius freezer (additional details provided in the Laboratory procedures study manual). 
j Collection of completed hot flash diary from subject (review for compliance) and new diary provided to subject. Diary records daily menopausal symptoms; hot flash frequency 
and severity; completed by subject twice daily (AM and PM) for duration of study. 
k Questionnaires completed by subject at clinic during indicated visit. 
l Study drug administration and randomization should occur at the completion of screening, after all eligibility is confirmed at the Baseline visit. 
m Coordinator-to-Subject phone calls will occur every week, except the weeks subjects are in clinic (Day 7 of the 14-day Run-in period, Weeks 1, 2, 5, 6, 9, 10, and 11) and will 
be documented. Subject is called as reminder to complete hot flash diary at same time twice-a-day (AM and PM) and document AEs. 30-day follow-up contact to inquire about 
subject status and record any AEs. 

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Appendix 2: Prohibited Drugs and Supplements 
• Drugs which may potentiate the release of neutrophils‚ such as lithium and 
corticosteroids (exception of nasal or other inhaled corticosteroids and OTC topical 
corticosteroids) 
• Any hormone therapy including oral contraceptives (natural or synthetic) 
• Selective serotonin reuptake inhibitors (SSRIs): 
• 
Citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, 
Seropram, Citox, Cital) 
• 
Dapoxetine (Priligy) 
• 
Escitalopram (Lexapro, Cipralex, Seroplex, Esertia) 
• 
Fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, 
Motivest, Flutop) 
• 
Fluoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox, 
Floxyfral) 
• 
Indalpine (Upstene) 
• 
Paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroat, Divarius, Rexetin, 
Xetanor, Paroxat, Loxamine, Deparoc) 
• 
Sertraline (Zoloft, Lustral, Serlain, Asentra) 
• 
Zimelidine (Zelmid, Normud) 
• Serotonin-norepinephrine reuptake inhibitors (SNRIs): 
• 
Venlafaxine (Effexor) 
• 
Desvenlafaxine (Pristiq) 
• 
Duloxetine (Cymbalta, Yentreve) 
• 
Milnacipran (Dalcipran, Ixel, Savella) 
• 
Sibutramine (Meridia, Reductil) 
• Gabapentin (Neurontin, Gralise) 
• Clonidine (Catapres, Jenloga, Kapvay) 
• Selective estrogen-receptor modulator (SERMs) 
• 
Clomifene 
• 
Femarelle 
• 
Ormeloxifene 
• 
Raloxifene 
• 
Tamoxifen 
• 
Toremifene 
• 
Lasofoxifene 
• Megestrol acetate (Megace) 
• Medroxyprogersterone acetate (Provera) 
• Methyldopa (Aldomet) 
• Pregabalin (Lyrica) 
• Anti-inflammatory biologics (such as the following): 
• 
Actemra  

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• 
Cimzia 
• 
Enbrel 
• 
Humira 
• 
Kineret 
• 
Orencia 
• 
Remicade 
• 
Rituxan 
• 
Simponi 
• Any supplements specifically used for hot flashes (such as the following): 
• 
Dong Quai 
• 
Epa (Eicosapentaenoic Acid) 
• 
Evening Primrose Oil 
• 
Flaxseed 
• 
Kudzu 
• 
Progesterone 
• 
Pycnogenol 
• 
Red Clover 
• 
Sage 
• 
Wild Yam 
• 
Black Cohosh 
• 
Magnesium 
• 
Soy products including proestrogens 
• 
Vitamin E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3: Hot Flash Related Daily Interference Scale

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Appendix 4: Insomnia Severity Index 

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Appendix 5: Menopause Specific Quality of Life Questionnaire  

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Appendix 6: Fatigue Severity Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 7: Arthritis Impact Measurement Scale