Does Subcutaneous Granulocyte Colony Stimulating Factor (G-CSF) Improve Ovarian Reserve in Women With Premature Ovarian Insufficiency?
Phase: PHASE2
Conditions: Primary Ovarian Insufficiency, Premature Ovarian Failure
Sponsor: Trio Fertility

 
 
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Does subcutaneous Granulocyte Colony Stimulating Factor (G-CSF) improve ovarian 
reserve in women with premature ovarian insufficiency? 
1.1 
Principal Investigator: Dr Robert Casper, TRIO Fertility 
1.2 
Study Site: TRIO Fertility 
 
HC protocol number TF005 
Background 
Women are born with all the eggs they will have in their lifetime which is estimated to be about 
two million. By puberty there are about four hundred thousand quiescent follicles remaining of 
which a small number initiate growth each month during a woman's reproductive life. Depletion 
of this primordial pool of follicles occurs over time, however the rate at which this occurs depends 
both on genetics (for instance accelerated in women with FMR-1 mutations) and environment (ie. 
exposure to chemotherapy or radiation therapy in the setting of cancer). Over time these women 
with premature ovarian insufficiency (POI), like women approaching age 50, can develop 
resistance to the signals from the brain that are involved in ovulation, disrupting their cycle and 
ultimately rendering fertility treatments such as IVF not effective.  
Premature ovarian insufficiency (otherwise known as premature menopause or premature ovarian 
failure) is defined as a state of elevated gonadotropins, hypoestrogenism and anovulatory cycles 
below 40 years old and impacts about 1 % of women [1]. Interestingly, patients who develop 
premature ovarian insufficiency post chemotherapy have been known to achieve spontaneous 
pregnancy after a bone marrow transplant [2,3,4]. This is thought to be related to bone marrow 
derived stem cells that could lead to recruitment of pre-existing quiescent follicles through various 
mechanisms including differentiation into oocyte-support cells (granulosa/theca/cumulus or 
stromal cells) and subsequent improved follicular environment, probable paracrine action via 
growth factor release and allowing for neovascularization and facilitation of blood perfusion to 
primordial follicles [5,6]. 
In fact, there is much evidence to suggest this is the case in both mouse models and human studies 
[6, 9-14]. In these studies, hematopoietic stem cells are either collected via direct aspiration from 
a patient's bone marrow (BM) or via a less invasive technique using granulocyte colony stimulating 
factor (G-CSF), which mobilizes stem cells from the BM into the peripheral blood. In the latter 
procedure, BM derived stem cells (BMDSC) are then collected through peripheral blood 
plasmapheresis using flow cytometry. In both instances, BMDSCs are either infused in the ovarian 
stroma of women with POI via laparoscopy or alternatively infused into the ovarian artery.  
In Herraiz et al 2018 [7], women who had diminished ovarian response (DOR) and considered as 
poor responders to gonadotropins were treated with G-CSF for 5 days at a mean dose of 600 mcg/d 
and peripheral blood was collected to isolate BMDSC and subsequently infused in one ovarian 
artery using the other ovary as control. The authors were able to show that autologous stem cell 
ovarian transplantation (ASCOT) post G-CSF treatment led to improvement in antral follicle count 

 
 
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and AMH levels in 81% of patients (13/16 patients). Overall comparing pre and post ASCOT IVF 
cycles they noted improvement in AFC, reduced cycle cancellation rate and better fertilization 
rates [7]. Noteworthy a total of 5 pregnancies occurred post ASCOT treatment (3 spontaneous) 
[7]. Interestingly, although they only infused stem cells into one ovarian artery they noted an effect 
on the control ovary as well suggesting that perhaps these stem cells and/or growth factors were 
able to travel through the blood stream and exert their function elsewhere. Hence, this raises the 
question of whether ovarian artery infusion is required at all, and if simply mobilizing BMDSC 
from BM into peripheral blood is sufficient to see these positive outcomes.  As a result, the same 
group performed a follow-up study or 10 women with POI undergoing ASCOT compared to 10 
women receiving only GCS-F (mean dose 600 mcg/d for 5 days) without apheresis and 
intraovarian artery infusion of hematopoietic stem cells (8). Both groups had similar results with 
6/10 women in each group having visible basal antral follicles, 2 in each group undergoing IVF 
and 1 patient having a single embryo transferred in each group.  This study suggests that intra-
ovarian artery infusion of stem cells is not required for folliculogenesis. Since both bone marrow 
aspiration and ASCOT are quite demanding and invasive procedures, we would like to confirm 
that treatment with G-CSF will lead to stem cell mobilization from the BM and this process alone 
will allow for improvement in markers of ovarian reserve in POI patients. G-CSF treatment is safe 
and has been routinely used in healthy donors for decades for the purpose of allogeneic stem cell 
transplants. We plan to use a lower dose of GCS-F (480 mcg/d for 4 days) 1 month apart for 2 or 
3 treatments. 
1.3         Primary Hypothesis 
We hypothesize that treatment of premature ovarian insufficiency patients with G-CSF to mobilize 
bone marrow hematopoietic stem cells will allow for improved ovarian reserve markers including 
antral follicle count, anti-mullerian hormone (AMH) levels and gonadotropin (FSH) levels. Our 
aim is to confirm and expand the results of Pellicer et al (8). 
Significance of the study: 
If this hypothesis is correct, G-CSF subcutaneous injection could be a simple, safe treatment for 
patients with POI to restore ovulation and improve fertility outcomes. 
Study Objectives: 
To determine if treatment with G-CSF will allow improvement in markers of ovarian reserve. 
Primary outcome –Decreased serum FSH and increased AMH levels and u/s measurement of 
increased antral follicle count (AFC) 
Secondary outcome – Improved ovarian response in IVF cycles if BAFs develop, and spontaneous 
or IVF pregnancy. 
Design: 
A pilot study. 

 
 
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1.4         Inclusion Criteria 
1) Women ages 25-40 
2)   Woman who meet criteria for POI defined as AFC < 5, AMH < 3 pmol/L and FSH >30 
IU/L. There may also be associated symptoms of the menopause such as hot flushes, night 
sweats, insomnia and vaginal dryness. 
3) Women who are not taking any other medical or fertility treatments except natural estrogen 
to stop hot flushes. 
4)   Informed consent 
 
1.5         Exclusion Criteria 
1)   Women with age > 40 
2)   Women with history of autoimmune disorders 
3)   Women with a history of hematopoietic cell malignancies  
4)   Women with sickle cell disease 
5)   Women with any other comorbidities that would preclude infertility treatment and 
pregnancy such as HIV/AIDS, hepatitis B or C, breast cancer or body mass index (BMI) >40. 
1.6         Recruitment 
Subjects will be identified by the investigators from the clinics at TRIO Fertility. Eligible study 
participant(s) will be given the consent form and approached in person by study personnel at the 
clinic. Subjects who express initial interest will be provided with detailed verbal and written 
information and they will be encouraged to consider the information at home also. They will be 
followed up by telephone call if they agree to being followed in this manner. 
Power Calculation: This is a pilot study, and we will recruit a total of 30 study participant(s). This 
number is based on the study of Pellicer et al (2020, ref 8) in which 10 women received G-CSF 
infusion alone without intra-arterial infusion of BM-derived stem cells and only one woman had 
an embryo transfer in IVF. We hope that 30 subjects will give us a better chance to see at least a 
10% response as in the previous study or better with the two monthly treatments.  
Study Methods and Procedures 

 
 
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1.7         Ethics 
This study will be conducted with adherence to the ethical principles that have their origins in the 
Declaration of Helsinki, the applicable guidelines for Good Clinical Practices (GCP), and the 
applicable laws and the Health Canada investigational testing regulations. 
1.7.1        Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
Approval from VERITAS IRB will be obtained before the recruitment of study subjects begins. 
All protocols (and applicable amendments, if any), including the subject information and consent 
form must be approved by the IRB before implementation. Appropriate reports on the progress of 
the study will be made by the investigator to the IRB, including any information on the completion 
or termination of the study. 
1.7.2        Subject Information and Consent 
The details of the study and consent forms will be provided by one of the study investigators who 
do not previously know the study participant(s). Information must be given in both verbal and 
written form. The subject consent form advises the participant that they are free to refuse their 
participation in or withdraw from the study at any time, without prejudice to the physician‑patient 
relationship or medical care provided. The participant will be encouraged to ask questions. The 
investigator will obtain and document informed consent from the participant. If additional medical 
releases are required for the access to diagnostic reports, these too will be obtained and maintained 
in the study files. The participant will be given copies of their subject information and consent 
form. The consent form will outline possible side effects of the G-CSF injections. See attached 
letter from Dr Keating who has 30 years’ experience using G-CSF in cancer patients and in healthy 
bone marrow donors. He describes bone pain, headache, nausea, fatigue and muscle pain as the 
most common side effects and these usually resolve with over-the-counter ibuprofen products. Dr 
Keating indicates that G-CSF is safe to use in healthy women although there have been reported 
rare but serious side effects such as splenic enlargement and rupture and inflammatory vascular 
complications like aortitis.  
 
1.7.3        Ethical Concerns 
Confidentiality – Dr. Casper will be custodian of patient data collected and will ensure that this 
data is appropriately protected with encryption and coded for analysis. No unnecessary patient 
information will be collected. 
Financial considerations – There will be no compensation for participating in this study. 
1.8         Study Timetable 
It is anticipated the study will commence pending ethics approval and be completed within 1 year. 

 
 
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1.8.1 Study Procedures 
Patients will be recruited in the study as outlined above. They will be given a SC injection of 0.5 
ml of G-CSF or filgrastim (Neupogen, Amgen, USA) at a concentration of 300 micrograms/day 
for 4 consecutive days. This is a typical dose used in healthy volunteers to allow for mobilization 
of stem cells in the setting of allogeneic stem cell transplantation. We have consulted Dr Armand 
Keating, head of hematologic oncology at Princess Margaret Hospital in Toronto who confirmed 
that the most common side effects reported from G-CSF treatment in healthy volunteers are 
aches/bone pains, headache and flu-like symptoms [15, 16]. Typically, these symptoms are mild 
to moderate and easily treated with over-the-counter analgesics (i.e.. ibuprofen or acetaminophen). 
G-CSF administration has been shown to cause a slight splenic enlargement which self-resolves 
in a few weeks [15]. We will monitor with abdominal ultrasound and routinely assess for persistent 
splenomegaly. In addition, leukocytosis is expected along with a mild decrease in platelet count 
and potassium, increase in uric acid, alkaline phosphatase, transaminases and lactate 
dehydrogenase levels in patients post G-CSF treatment [16] and hence we will monitor these levels 
as well. The first SC injection will be given in the office by our nursing staff. Patients will be kept 
under observation for 60 mins. Subsequent injections can be self-administered by the patient at 
home. Neupogen comes in prefilled syringes of 0.5 ml containing 300 mcg of filgrastim. The 
syringes can be kept at room temperature for 14 days and will be provided in an opaque envelop 
to prevent light exposure. The patients will be shown how to administer the Neupogen 
subcutaneously by the nurse (most subjects have experience with subcutaneous injections from 
their infertility treatments). They will be instructed to inject the full syringe contents daily at the 
same time as their first injection for three days and then return to TRIO for monitoring the 
following day. The procedure, including monitoring for WBC count, FSH, AMH, pelvic u/s for 
basal antral follicle count and splenic u/s and 4 days of SC injections of Neupogen will be repeated 
in one month. 
Monitoring 
Baseline monitoring prior to G-CSF injections will include CBC, liver function tests, electrolytes, 
abdominal and pelvic u/s, and endocrine screening including LH, FSH, E2 and progesterone plus 
AMH. All tests except AMH and BAF count will be repeated at each visit to TRIO and after each 
set of 4 injections. AMH and BAF counts will be repeated at the end of 2 months. (See uploaded 
Excel spreadsheet for monitoring schedule).  
Patients will be offered two rounds of G-CSF treatment one month apart. If no response is seen 
(improvement in gonadotropin and anti-mullerian levels as well as antral follicle count) then we 
will provide the patient with the option of a third treatment a month later. Follow-up by blood 
assessment of AMH and FSH and u/s measurement of BAF count will continue for 3months after 
the last GCS-F infusion. 
1.8.2 Study Visits 
Baseline testing will include CBC, endocrine screen (FSH, LH, estrogen, progesterone), markers 
of ovarian reserve (US for AFC count, AMH levels) and monitoring of liver function tests (ALT, 
AST, ALP, LDH), kidney function (creatinine, sodium, potassium, uric acid) and lastly US to 

 
 
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check for splenic enlargement. This will be done prior to the first Neupogen injection and on day 
five (one day after the fourth SC G-CSF injection).  
Patients will return one month after the first series if injections (day 30 of study) and repeat all the 
testing. Another round of G-CSF treatment will be administered (4 days of SC injections) and 
testing will occur again on day 35. Patient will again return one month after (day 60 of the study) 
and repeat all testing. If no response is seen, then the patient will be offered a third round of G-
CSF injections with testing on day 65 and day 90 of study.  
1.8.3 Outcome Measures 
 
Primary outcomes –Success of the treatment will be assessed by a reduction in serum FSH, an 
increase in AMH (measure of ovarian reserve) and u/s measurement of an increased number of 
antral follicles (AFC). If an increased number of basal antral follicles is seen in association with 
an FSH level below 20 IU/L, the subjects will be offered a cycle of IVF to see if oocytes and 
subsequently embryos can be obtained. 
Secondary outcomes – improved ovarian response in IVF cycles if BAFs develop, and spontaneous 
or IVF pregnancy 
 
Significance 
Women with POF are young and most want to have a family. At present, there is no alternative for 
these women to conceive except to use donor eggs, either from a friend or relative, or more 
commonly, from an anonymous egg donor bank or service in the United States or Europe since 
payment for donor eggs in Canada is illegal. If the results of this study are positive for development 
of new follicles in the ovaries of women with POF, it might be possible for them to use their own 
eggs in order to conceive, either naturally or through IVF. This opportunity would represent a 
major benefit both emotionally and financially. 
Discontinuation Criteria 
The following issues will result in a subject being withdrawn from the study and all existing study 
data including that obtained from withdrawn subjects will be retained. 
1) Late determination of ineligibility – Subjects who are subsequently determined not to be 
eligible for inclusion based on the study protocol inclusion/exclusion criteria set for that 
study stage or withdraw their consent will be excluded. 
2) Patient request. 

 
 
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1.9 Safety Parameters 
 
1.9.1        Risk-Benefit Estimate 
The time commitment for subjects will be minimal, because the consent forms will be signed 
during the regular planned visits at the clinic. Study participant(s) may benefit regarding their 
fertility potential if a positive response is seen with G-CSF treatment. We plan to use a lower dose 
of G-CSF (300 mcg/d x 4 days) compared to the study of Pellicer et al (8) (600 mcg/d x 5 days) 
but with repeated treatments monthly for 2-3 months. If subjects complain of any worrisome side 
effects, they will be withdrawn from the study after the first month. The product monograph 
outlining side effects is uploaded with the application. 
 
Knowledge Transfer 
All results will be disseminated in the form of peer–reviewed or open-access publications as well 
as presentations at national and international expert meetings. 
Essential Documentation 
The Principal Investigator will sign the protocol to document their willingness to adhere to this 
protocol and to conduct the study in accordance with local legal requirements and the International 
Conference on Harmonization (ICH) guidelines for GCP. 
 
References: 
1. Guideline 
on 
the 
management 
of 
premature 
ovarian 
insufficiency. 
(n.d.). 
https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-
ovarian-insufficiency. 
2. Hershlag, A., & Schuster, M. W. (2002). Return of fertility after autologous stem cell 
transplantation. Fertility and Sterility, 77(2), 419–421. 
3. Merloni, A., Hawley, J., Levy, W. C., Gooley, T., Cd, B., Deeg, H. J., Doney, K., Storb, 
R., Sullivan, K. M., Witherspoon, R. P., & A. (1996). Pregnancies following high-dose 
cyclophosphamide with or without high- dose busulfan or total-body irradiation and bone 
marrow transplantation. Blood, 87(7), 3045–3052. 
4. Salooja, N., Szydlo, R., Socié, G., Rio, B., Chatterjee, R. M., Ljungman, P., Van Lint, M. 
T., Powles, R. L., Jackson, G., Hinterberger-Fischer, M., Kolb, H., & Apperley, J. F. 
(2001). Pregnancy outcomes after peripheral blood or bone marrow transplantation: a 
retrospective survey. The Lancet, 358(9278), 271–276.  
5. Tandulwadkar, S., & Karthick, M. S. (2020). Combined use of autologous bone marrow-
derived stem cells and platelet-rich plasma for ovarian rejuvenation in poor responders. 
Journal of Human Reproductive Sciences, 13(3), 184.  

 
 
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6. Buigues, A., Marchante, M. C. F., De Miguel-Gómez, L., Martinez, J. A., Cervelló, I., 
Pellicer, A., & Herraiz, S. (2021). Stem cell–secreted factor therapy regenerates the ovarian 
niche and rescues follicles. American Journal of Obstetrics and Gynecology, 225(1), 65.e1-
65.e14.  
7. Herraiz, S., Romeu, M., Buigues, A., Rodríguez, S., Diaz-Garcia, C., Gómez-Seguí, I., 
Martínez, J. L., Pellicer, N., & Pellicer, A. (2018). Autologous stem cell ovarian 
transplantation to increase reproductive potential in patients who are poor responders. 
Fertility and Sterility, 110(3), 496-505.e1. 
8. Pellicer, N, Herraiz, S, Romeu, M, Martinez, S, Buiges, A, Gomez-Seguí, I, Martínez, J, 
Pellicer, A., 2020. Bone marrow derived stem cells restore ovarian function and fertility in 
women with POI: Interim report of a randomized trial comparing mobilization versus 
ovarian injection. 36th Annual Meeting of European Society Reproduction and 
Embryology (ESHRE).  
9. Andaloussi, A. E., Igboeli, P., Amer, A., & Al-Hendy, A. (2018). Intravenous Infusion of 
Nucleated Peripheral Blood Cells Restores Fertility in Mice with Chemotherapy-Induced 
Premature Ovarian Failure. Biomedicines, 6(3), 93.  
10. Edessy, M., Hosni, H. N., Shady, Y. A., Waf, Y., Bakr, S., & Kamel, M. M. (2015). 
Autologous stem cells therapy, The first baby of idiopathic premature ovarian failure. Acta 
Medica International, 3(1), 19.  
11. Gupta, S., Lodha, P., Karthick, M. S., & Tandulwadkar, S. (2018). Role of autologous bone 
marrow-derived stem cell therapy for follicular recruitment in premature ovarian 
insufficiency: Review of literature and a case report of world’s first baby with ovarian 
autologous stem cell therapy in a perimenopausal woman of age 45 year. Journal of Human 
Reproductive Sciences, 11(2), 125. 
12. He, Y., Chen, D., Yang, L., Qiaoni, H., Ma, H., & Xu, X. (2018). The therapeutic potential 
of bone marrow mesenchymal stem cells in premature ovarian failure. Stem Cell Research 
& Therapy, 9(1), 263. 
13. Mashayekhi, M., Mirzadeh, E., Chekini, Z., Ahmadi, F., Eftekhari-Yazdi, P., Vesali, S., 
Madani, T., & Aghdami, N. (2021). Evaluation of safety, feasibility and efficacy of intra-
ovarian transplantation of autologous adipose derived mesenchymal stromal cells in 
idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first 
in human. Journal of Ovarian Research, 14(1).  
14. Herraiz, S., Buigues, A., Diaz-Garcia, C., Romeu, M., Rodríguez, S., Gómez-Seguí, I., 
Simón, C., Hsueh, A. J. W., & Pellicer, A. (2018). Fertility rescue and ovarian follicle 
growth promotion by bone marrow stem cell infusion. Fertility and Sterility, 109(5), 908-
918.e2.  
15. Yang, B., & Kido, A. (2011). Pharmacokinetics and Pharmacodynamics of Pegfilgrastim. 
Clinical Pharmacokinectics, 50(5), 295–306.  
16. Hölig, K. (2013). G-CSF in Healthy Allogeneic Stem Cell Donors. Transfusion Medicine 
and Hemotherapy, 40(4), 225–235.  
 
 
 

 
 
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TRIO Fertility 
CONSENT FORM 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
  
Title: Does subcutaneous Granulocyte Colony Stimulating Factor (G-CSF) improve ovarian 
reserve in women with premature ovarian insufficiency? 
Investigator: Dr R. Casper 
The investigator can be contacted by phone: 416-506-0804 x3228 or Fax: 416-972-0036 
Introduction 
You are being asked to participate in this study because you meet pre-determined study criteria 
that define premature ovarian insufficiency. Please read this explanation about the study and its 
risks and benefits before you decide if you would like to take part. You should take as much time 
as you need to make your decision. You should ask the study doctor or study staff to explain 
anything that you do not understand and make sure that all your questions have been answered 
before signing this consent form. Before you make your decision feel free to talk about this study 
with anyone you wish. Participation in this study is voluntary. 
Background 
Women are born with all the eggs they will have in their lifetime which is estimated to be about 
two million. By around puberty, there are about 400,000 follicles left (follicle refers to the egg and 
surrounding cells). Once you reach puberty, several follicles are recruited each month of which 
you only typically ovulate one. During a woman’s reproductive life, follicle are used up over time 
and at menopause there about 1000 or fewer follicles remaining.  
In premature ovarian insufficiency, this process occurs much faster for reasons unknown. In 
addition, women can develop resistance to the signals from the brain that are involved in ovulation 
hence disrupting their cycle.  
Patients who developed premature ovarian insufficiency after chemotherapy have been known to 
achieve spontaneous pregnancy after a bone marrow transplant. This observation is thought to be 
related to bone marrow derived stem cells producing factors that could lead to the waking up of 
pre-existing dormant or unresponsive follicles (eggs).  

 
 
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Granulocyte colony stimulating factor (G-CSF) mobilizes certain stem cells from the bone marrow 
in the blood and is routinely used in healthy patients who will be donors before a stem cell 
transplant. It is possible that mobilizing bone marrow stem cells with G-CSF could work the same 
way as a bone marrow transplant to wake up resting follicles in the ovary. If you agree to participate 
in this study, you will have baseline blood work and ultrasound and four G-CSF injections under 
the skin each month for three months. You will have monitoring by blood draw and ultrasound 
before and after every series of 4 daily injections. You will be a part of a group of 30 patients 
participating in the study. 
 Purpose 
The purpose of this study is to compare your ovarian follicle count (reflecting the presence of eggs 
that could be stimulated by fertility drugs) and measures of markers of active ovarian follicles 
before and after treatment with G-CSF.  
Procedures 
You are being asked to participate in this study because you meet pre-determined study criteria 
that define premature ovarian insufficiency. If you agree to participate, you will receive 4 G-CSF 
injections under the skin each month for 2 or possibly 3 months. You will receive the first injection 
in the office and you will be trained to do subsequent injections at home by one of our nurses if 
you are comfortable with doing the injections. You will be shown by a nurse how to administer 
the G-CSF by needle under the skin. The G-CSF comes in preloaded syringes for ease of 
administration. The syringes can be stored at room temperature in the provided envelop to protect 
the solution from light exposure. Each injection should be done daily at about the same time as the 
first injection and for three days. Alternatively, a nurse at your closest Trio location could do the 
injection for you. You will be monitored with blood work and ultrasound before and after treatment 
each month. You will have access to the study investigator if you have any concerns with regards 
to the study or think you are experiencing side effects.  
Risks 
G-CSF has been developed as a treatment for patients with blood cancers. However, it is now 
standard practice to administer G-CSF to healthy individuals, both men and women, in order to 
get stem cells to leave the bone marrow and enter the bloodstream where they can be collected and 
used for a bone marrow transplant for another person who is ill. In the present study, we will be 
using the G-CSF for the same reason that it is given to heathy bone marrow donors. In this study, 
we want to get your bone marrow stem cells into the blood so they can interact with your ovaries 
and possible awaken resting eggs. The most common side effects reported from G-CSF treatment 
in healthy subjects are muscle aches, bone pains, fatigue, headache and flu-like symptoms.  
Also, patients may commonly experience redness, swelling, or itching at the site of injection. 

 
 
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Typically, these symptoms are mild to moderate and easily treated with over-the-counter 
medications such as the pain-relievers ibuprofen or acetaminophen. G-CSF administration may 
cause slight spleen enlargement which usually resolves in a few weeks and hence we will also 
monitor you with an abdominal ultrasound to measure the size of your spleen before and after 
treatment. There have been reported some rare complications listed below: 
Possible serious side effects from using NEUPOGEN 
 
These are not all the possible side effects that you may experience when taking NEUPOGEN. A 
table with other very rare but serious side effects is attached at the end of this consent form. If you 
experience any side effects whether listed here or not, please let Dr Casper know. 
. 
• Spleen Rupture. Your spleen may become enlarged and can rupture while taking NEUPOGEN. 
A ruptured spleen can cause death. The spleen is located in the upper left section of your stomach 
area. Call your doctor right away if you or your child has pain in the left upper stomach area or 
left shoulder tip area. This pain could mean you or your child’s spleen is enlarged or ruptured. 
• Serious Allergic Reactions. NEUPOGEN can cause serious allergic reactions. These reactions 
can cause a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around 
the mouth or eyes, fast pulse, and sweating. If you or your child starts to have any of these 
symptoms, stop using NEUPOGEN and call your doctor or seek emergency care right away. If 
you or your child has an allergic reaction during the injection of NEUPOGEN, stop the injection 
right away. 
• A serious lung problem called acute respiratory distress syndrome (ARDS). Call your doctor 
or seek emergency care right away if you or your child has shortness of breath, trouble breathing 
or a fast rate of breathing. 
• Sickle Cell Crisis. Call your doctor or seek emergency care right away if you experience severe 
pain in bones, chest, gut or joints. 
• Kidney injury (glomerulonephritis) has been seen in patients who received NEUPOGEN. Call 
your doctor right away if you experience puffiness in your face or ankles, blood in your urine or 
brown coloured urine, or if you notice that you urinate less often than usual. 
 
 
Benefits 
You may not receive any direct benefit from being in this study. In the case our hypothesis is 
correct, you may have a greater number of follicles as well as improved ovarian markers of egg 
count in the ovary. If there are an increased number of follicles seen on ultrasound and if your FSH 
levels are less than 20 IU/L, you will be offered an IVF cycle if you wish. You may also be able 
to get pregnant naturally. In addition, information learned from this study may help other people 
with infertility in the future.  
  
Voluntary Participation 

 
 
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Your participation in this study is voluntary. If you consent to participate, you can withdraw your 
participation at any time. 
If any other research information becomes available which may be relevant to your care, you will 
be informed of this in a timely manner. 
Alternatives to Being in the Study 
You do not have to join this study to receive the regular treatment and refusing to participate in 
the study will not influence any current treatment decisions.  The standard infertility treatment for 
premature ovarian insufficiency is the use of donor eggs in order to get pregnant. 
Confidentiality 
If you agree to join this study, the study doctor and his/her study team will look at your personal 
health information and collect only the information they need for the study.  Personal health 
information is any information that could be used to identify you and includes your: 
·         name, address, date of birth, and new or existing medical records,that includes types, dates 
and results of medical tests or procedures.  
The information that is collected for the study will be kept in a locked and secure area by the study 
doctor for 15 years.  Only the study team or the people or groups listed below will be allowed to 
look at your records.  Your participation in this study also may be recorded in your medical record 
at TRIO.  
All information collected during this study, including your personal health information, will be 
kept confidential and will not be shared with anyone outside the study unless required by law.  The 
data will be stored in an electronic medical record that is password protected and only your doctor 
and research staff will have access to the data. As with any virtual platform of data storage, there 
is a potential risk of a data breach. You will not be named in any reports, publications, or 
presentations that may come from this study.  
If you decide to leave the study, the information about you that was collected before you left the 
study will still be used.  No new information will be collected without your permission. 
Expenses Associated with Participating in the Study 
 No compensation will be provided for any routine costs experienced by you during the study. 
 
 

 
 
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Conflict of Interest 
  
Dr. Casper is a founding partner of TRIO Fertility and benefits financially from all activities at the 
clinic including IVF. You should not feel pressured or coerced to join this study. 
In Case You Are Harmed in this Study 
If you become ill, injured or harmed as a result of taking part in this study, you will receive care. 
The costs of any medical treatment not covered by your Provincial Health Insurance plan or 
Medical Insurance plan will be covered. No other form of reimbursement for study-related injury 
or illness is offered. In no way does signing this consent form waive your legal rights nor does it 
relieve the investigators, sponsors or involved institutions from their legal and professional 
responsibilities. You do not give up any of your legal rights by signing this consent form. This 
study has been reviewed and approved by Veritas Independent Review Board (IRB). If you have 
any questions about your rights as a research participant or the Investigator's responsibilities, you 
may contact the Manager of Veritas IRB 24 hours per day and 7 days per week at 514-337-0442 
or toll-free at 1-866-384-4221. An IRB is a group of scientific and non-scientific individuals who 
perform the initial and ongoing ethical review of the research study with the subject's rights and 
welfare in mind. If you have any study-related comments, complaints or concerns, you should first 
contact the study investigator. Please call the IRB if you need to speak to a person independent 
from the Investigator and the research staff, and /or if the Investigator and the research staff could 
not be reached. 
  
Questions 
If you have any questions, concerns or would like to speak to the study team for any reason, please 
call 416 506-0804 x2353. 
 
 
 
 
 

 
 
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Consent 
This study has been explained to me and any questions I had have been answered. I know that I 
may leave the study at any time. I agree to take part in this study. 
  
                                                      
                                                      
                               
Print Study Participant’s Name               
Signature                           
Date 
  
  
                                                      
                                                      
                               
Witness’s Name                            
        
Signature                           
Date 
  
  
(You will be given a signed copy of this consent form) 
  
My signature means that I have explained the study to the participant named above. I have 
answered all questions. 
  
  
                                                               
   
                                          
                            
Print Name of Person Obtaining Consent                    Signature                               Date 
  
  
  

 
 
Version 4, July 15, 2023 
 
 
 

 
 
Version 4, July 15, 2023