A Study of the Safety and Effect of Repeated Administration of G-CSF on Hot Flashes in Postmenopausal Women

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of repeated administration of G-CSF for the treatment of hot flashes and vasomotor symptoms in women with naturally-occurring or surgically induced menopause. G-CSF will be administered three times at 28 day intervals to postmenopausal women, ages 40 to 65, suffering at least 49 moderate to severe hot flashes per week.

Detailed Description
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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 G-CSF or placebo. This study will consist of a 14-21 day screening period. Subjects enrolled will be given three single 1.0 mL subcutaneous (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 complete blood count with differential) and vital signs. A follow-up phone call will occur 60 days after the last dose of study drug. Eligibility will be assessed via physical examination, clinical laboratory testing, vital signs. Subjects will receive a diary in which to record daily hot flashes symptoms during the duration of the screening period. Subjects must have at least 14 days of hot flash recordings to participate in the study. The diary will be reviewed by study site staff on Baseline (Day 0) to confirm study eligibility. During the treatment period, subjects will return to the study site at Days 1, 21, 28, 29, 49, 56, 57, and 84 for assessments. The follow-up phone call will occur approximately 60 days following the last dose of study drug.

Official Title
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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

Conditions
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Postmenopausal Symptoms

Intervention / Treatment
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* Biological: G-CSF
* Other: Placebo/Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: 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 >40 IU/L) Surgically postmenopausal is defined as at least 3 months after documented bilateral salpingo oophorectomy Normal pelvic exam and pap smear within 2 years Signed informed consent Exclusion Criteria: Radiation or chemotherapy-induced (including gonadotropin-releasing hormone (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 selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (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 over-the-counter (OTC) hydrocortisone ointment or cream 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 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 Follicle stimulating hormone (FSH) < 40 IU/L or 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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental: G-CSF<br>Intervention: G-CSF given by subcutaneous injection repeated 3 times (Days 0, 28, 56) Other name: Filgrastim | Biological: G-CSF<br>* G-CSF injected subcutaneously 3 times (Days 0, 28, 56)<br>* Other names: Filgrastim;|
| Placebo Comparator: Comparator: Placebo/Saline<br>Intervention: Placebo/saline given by subcutaneous injection repeated 3 times (Days 0, 28, 56) Other name: Saline | Other: Placebo/Saline<br>* Placebo/saline injected subcutaneously 3 times (Days 0, 28, 56)<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | 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. 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. | From first dose date up to 30 days after last dose (up to 16 weeks) | 
| Change From Baseline in White Blood Cell Counts 24 Hours After Administration of G-CSF or Placebo on Day 0 | Change from baseline in white blood cell counts 24 hours after administration of G-CSF or placebo on day 0. Blood samples were collected 24 hours after adminstration of G-CSF on day 0. | Baseline and day 1 | 
| Change From Baseline in White Blood Cell Counts 24 Hours After Administration of G-CSF or Placebo on Day 28 | Change from baseline in white blood cell counts 24 hours after administration of G-CSF or placebo on day 28. Blood samples were collected 24 hours after adminstration of G-CSF on day 28. | Baseline and day 29 | 
| Change From Baseline in White Blood Cell Counts 24 Hours After Administration of G-CSF or Placebo on Day 56. | Change from baseline in white blood cell counts 24 hours after administration of G-CSF or placebo on day 56. Blood samples were collected 24 hours after adminstration of G-CSF on day 56. | Baseline and day 57 | 
| Change From Baseline in White Blood Cell Counts on Day 84 (28 Days After Last Administration of G-CSF or Palcebo) | Change from baseline in white blood cell counts on day 84. Blood samples were collected 24 hours after adminstration of G-CSF on day 84. | Baseline and day 84 | 
| Change From Baseline in the Mean Frequency of Moderate and Severe (M+S) Hot Flashes at Week 4 | The frequency of moderate to severe hot flashes was the number of moderate to severe hot flashes per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and week 4 | 
| Change From Baseline in the Mean Frequency of Moderate and Severe (M+S) Hot Flashes at Week 12 | The frequency of moderate to severe hot flashes was the number of moderate to severe hot flashes per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and week 12 | 
| Change From Baseline in the Mean Composite Daily Severity of Hot Flashes (CDS) at Week 4 | CDS (Composite Daily Hot Flash Severity) was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and week 4 | 
| Change From Baseline in the Mean Composite Daily Severity of Hot Flashes (CDS) at Week 12 | CDS (Composite Daily Hot Flash Severity) was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and week 12 | 
| Change From Baseline in the Mean Daily Severity of Hot Flashes (HFSS) at Week 4 | HFSS (Daily Hot Flash Severity Score) was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]/daily total hot flashes), where total hot flashes (THF) = number of daily mild, moderate, and severe hot flashes. A daily severity score per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and week 4 | 
| Change From Baseline in the Mean Daily Severity of Hot Flashes (HFSS) at Week 12 | HFSS (Daily Hot Flash Severity Score) was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]/daily total hot flashes), where total hot flashes (THF) = number of daily mild, moderate, and severe hot flashes. A daily severity score per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving >50% Reduction in the Mean Frequency of Moderate and Severe (M+S) Hot Flashes up to Week 12 | The frequency of moderate to severe hot flashes was the number of moderate to severe hot flashes per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Weeks 1-12 | 
| Number of Subjects Acheiving >50% Reduction in the Mean Composite Daily Hot Flash Severity (CDS) up to Week 12 | CDS was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Weeks 1-12 | 
| Number of Subjects Acheiving >0.30 Reduction in the Mean Daily Hot Flash Severity Score (HFSS) up to Week 12 | HFSS was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]. HFSS = ((number of daily mild hot flashes x1) + (number of daily moderate hot flashes x2) + (number of severe hot flashes x3))/daily total hot flashes), where total hot flashes (THF) = number of daily mild, moderate, and severe (S) hot flashes. A daily severity score per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. Severity was zero for participants that had no mild or moderate or severe VMS. Higher scores indicates greater severity. | Weeks 1-12 | 
| Percent Change in M+S at 12 Weeks in Demographic Subgroups | The frequency of moderate to severe hot flashes was the number of moderate to severe hot flashes per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received. | Baseline and Week 12 | 
| Net Change in HFSS at 12 Weeks in Demographic Subgroups | HFSS (Daily Hot Flash Severity Score) was calculated as follows: [(number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3)]. HFSS = ((number of daily mild hot flashes x1) + (number of daily moderate hot flashes x2) + (number of severe hot flashes x3))/daily total hot flashes), where total hot flashes (THF) = number of daily mild, moderate, and severe (S) hot flashes. A daily severity score per week was derived by taking the mean of the data over 7 days. All subjects who were randomized and received at least one dose of study drug are included in this subset. Subjects are analysed according to the randomized treatment group regardless of treatment received | Baseline and Week 12 | 
| Net Change in MENQOL VMS Score | Menopause-specific Quality of Life (MENQOL) Questionnaire. The MENQOL is self-administered and consists of a total of 29 items in a Likert-scale format. Each item assesses the impact of one of four domains of menopausal symptoms, as experienced over the last month: vasomotor (items 1-3), psychosocial (items 4-10), physical (items 11-26), and sexual (items 27-29). MENQOL VMS refers to the answers to items 1-3 where 6 = most bothersome and 0 = least bothersome). (Maximum bothersomeness = 18; No bothersomeness = 0) | Baseline and week 12 | 
| Net Change in HFRDIS Score | The Hot Flash Related Daily Interference Scale (HFRDIS) measures (as a score of 0 to 10) the effect of hot flashes on overall quality of life and on nine specific activities: work, social activities, leisure activities, sleep, mood, concentration, relations with others, sexuality, and enjoyment of life. The 10 answers are added up to get a total score. HFRDIS Score (Maximum Bothersomness = 100; No Bothersomeness = 0). The higher the score, the more bothersome the symptoms. | Baseline and week 12 | 
| Net Change in ISI Score at 12 Weeks | The Insomnia Severity Index has seven questions. For each question, most bothersome = 4; not bothersome = 0. The seven answers are added up to get a total score. Total score categories: 0-7 = No clinically significant insomnia; 8-14 = Subthreshold insomnia; 15-21 = Clinical insomnia (moderate severity); 22-28 = Clinical insomnia (severe) | Baseline and week 12 | 
| Net Change in FSS Score at 12 Weeks | Fatigue Severity Scale (FSS) of Sleep Disorders. The Fatigue Severity Scale (FSS) is a method of evaluating the impact of fatigue. The FSS is a short questionnaire (10 questions) that requires the subject to rate level of fatigue. The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms. Each statement is read and the corresponding number from 1 to 7 is circled. A low value (e.g., 1) indicates strong disagreement with the statement, whereas a high value (e.g., 7) indicates strong agreement. (Maximum bother = 70; No bother = 0) | Baseline and week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hot Flashes, Vasomotor Symptoms, Menopause