Faslodex in McCune Albright Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, effectiveness and pharmacokinetics of a study drug called Faslodex (fulvestrant) in the treatment of progressive precocious puberty (early puberty) in girls with McCune-Albright syndrome (MAS)

Official Title
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An Open-label, Non-Comparative Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of Faslodex (Fulvestrant) in Girls With Progressive Precocious Puberty Associated With McCune-Albright Syndrome

Conditions
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Puberty, Precocious, McCune-Albright Syndrome

Intervention / Treatment
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* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females less than or equal to 10 years of age (prior to 11th birthday) Diagnosis of McCune-Albright syndrome (MAS) Progressive precocious puberty (PPP) associated with MAS Exclusion Criteria: Received any prior treatment for PPP associated with MAS with fulvestrant Abnormal platelet count or liver function tests Bleeding disorders Long term anticoagulation therapy Known hypersensitivity to any component of the study drug

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 10 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Fulvestrant<br>* intramuscular injection<br>* Other names: ZD9238;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Frequency of Annualised Days of Vaginal Bleeding | Change in the frequency of annualised days of vaginal bleeding during the 12 month treatment period compared to the 6 month baseline period, based on a worst-case scenario calculation .i.e. missing diary card days counted as bleeding days. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Baseline Vaginal Bleeding Who Experienced ≥50% Reduction in the Number of Vaginal Bleeding Days | Percentage of participants with baseline vaginal bleeding who experienced ≥50% reduction in the number of vaginal bleeding days during the 12 month treatment period compared to the 6 month baseline period. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over a 6 Month Trial Period. | Percentage of participants with baseline vaginal bleeding who experienced cessation of vaginal bleeding for at least 180 consecutive days during the 12 month treatment period, based on a worst-case approach i.e. missing diary card days counted as bleeding days. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding . | Percentage of participants with baseline vaginal bleeding who experienced cessation of vaginal bleeding for the full 12 month treatment period, based on a worst-case approach i.e. missing diary card days counted as bleeding days. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Change in Bone Age Advancement Over the First 6 Month Trial Period. | Change in the rate of increase in bone age from pre treatment (based on the 6 month retrospective visit) to the first 6 months of the treatment period. Bone age advancement for a particular time period was calculated as the increase in bone age over that time period adjusted (ie, normalized) for the length of that time period. | baseline to first 6 months of the treatment period | 
| Change in Bone Age Advancement Over the Second 6 Month Trial Period. | Change in the rate of increase in bone age from pre treatment (based on the 6 month retrospective visit) to the second 6 months of the treatment period. Bone age advancement for a particular time period was calculated as the increase in bone age over that time period adjusted (ie, normalized) for the length of that time period. | baseline to second 6 months of the treatment period. | 
| Change in Bone Age Advancement Over the Whole 12 Month Trial Period. | Change in the rate of increase in bone age from pre treatment (based on the 6 month retrospective visit) to the full 12 month treatment period. (Using last value carried forward method for the one patient who withdrew soon after their month 6 bone scan) Bone age advancement for a particular time period was calculated as the increase in bone age over that time period adjusted (ie, normalized) for the length of that time period. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Change in Growth Velocity (Annualised Growth Velocity i.e. cm/y) Over the First 6 Month Trial Period. | Change in growth velocity (annualised growth velocity.i.e. cm/y) from the pre treatment period to the first 6 months of the treatment period. Growth velocity for a particular time period was calculated as the increase in height over that time period divided by the length of that time period (expressed in cm/year) | 6 month pre-treatment observation period (baseline) followed by 6 month treatment period (on treatment period) | 
| Change in Growth Velocity (Annualised Growth Velocity i.e. cm/y) Over the Second 6 Month Trial Period. | Change in growth velocity (annualised growth velocity i.e. cm/y) from the pre treatment period to the second 6 months of the treatment period. Growth velocity for a particular time period was calculated as the increase in height over that time period divided by the length of that time period (expressed in cm/year) | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Change in Growth Velocity (Annualised Growth Velocity i.e. cm/y) Over the Whole 12 Month Trial Period. | Change in growth velocity (annualised growth velocity i.e. cm/y) from the pre treatment period to the full 12 month treatment period. Growth velocity for a particular time period was calculated as the increase in height over that time period divided by the length of that time period (expressed in cm/year) | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Change in Growth Velocity (Z-Score) Over the First 6 Month Trial Period. | Change from pre-treatment period to the first 6 months of the treatment period. Z-score is [(growth velocity from the previous visit to the current visit - mean) / standard deviation(SD)], where the mean and SD are from the National Center for Health Statistics, Fels study. | 6 month pre-treatment observation period (baseline) followed by 6 month treatment period (on treatment period) | 
| Change in Growth Velocity (Z-Score) Over the Second 6 Month Trial Period. | Change in growth velocity (Z-Score) from pre-treatment to the second 6 months of the treatment period. Z-score is [(growth velocity from the previous visit to the current visit - mean) / standard deviation(SD)], where the mean and SD are from the National Center for Health Statistics, Fels study. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Change in Growth Velocity (Z-Score) Over the Whole 12 Month Trial Period. | Change in growth velocity (Z-Score) from pre-treatment to the full 12 month treatment period. Z-score is [(growth velocity from the previous visit to the current visit - mean) / standard deviation(SD)], where the mean and SD are from the National Center for Health Statistics, Fels study. | 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on treatment period) | 
| Change in Uterine Volume From Baseline to Month 12 by Ultrasound. | Uterine volume was calculated via ultrasound using the formula: 0.5(longitudinal multiplied by anteroposterior multiplied by transverse), if all 3 linear dimensions were recorded. If all 3 linear dimensions were not recorded, uterine volume was not calculated. | Screening visit (baseline) and Month 12 during the treatment period. | 
| Change in Uterine Volume From Baseline to Month 6 by Ultrasound. | Uterine volume was calculated via ultrasound using the formula: 0.5(longitudinal multiplied by anteroposterior multiplied by transverse), if all 3 linear dimensions were recorded. If all 3 linear dimensions were not recorded, uterine volume was not calculated. | Screening visit (baseline) and Month 6 during the treatment period. | 
| Change in Uterine Volume From Month 6 to Month 12 by Ultrasound. | Uterine volume was calculated via ultrasound using the formula: 0.5(longitudinal multiplied by anteroposterior multiplied by transverse), if all 3 linear dimensions were recorded. If all 3 linear dimensions were not recorded, uterine volume was not calculated. | Month 6 and Month 12 during the treatment period. | 
| Change in Ovarian Volume From Baseline to Month 12 by Ultrasound. |  | Screening visit (baseline), Months 6 and 12 during the treatment period. | 
| Change in Ovarian Volume From Baseline to Month 6 by Ultrasound. |  | Screening visit (baseline), Months 6 and 12 during the treatment period. | 
| Change in Ovarian Volume From Month 6 to Month 12 by Ultrasound. |  | Screening visit (baseline), Months 6 and 12 during the treatment period. | 
| Hormone Assays: Serum Oestradiol. | Hormone assays: serum oestradiol at Screening visit (baseline), Month 12 of the treatment period. Results presented relate to Month 12 of the treatment period. | Month 12 of the treatment period. | 
| Hormone Assays: Luteinizing Hormone (LH). | Hormone assays: Luteinizing hormone (LH) at Screening visit (baseline), Month 12 of the treatment period. Results presented relate to Month 12 of the treatment period. | Month 12 of the treatment period. | 
| Hormone Assays: Follicle-stimulating Hormone (FSH). | Hormone assays: follicle-stimulating hormone (FSH)at Screening visit (baseline), Month 12 of the treatment period. Results presented relate to Month 12 of the treatment period.. | Month 12 of the treatment period. | 
| Hormone Assays: Testosterone. | Hormone assays: testosterone at Screening visit (baseline), Month 12 of the treatment period. Results presented relate to Month 12 of the treatment period.. | Month 12 of the treatment period. | 
| PK: Mean Clearance. | Mean clearance is the average amount of Fulvestrant which is eliminated | Throughout the 12 month treatment period. | 
| PK: Mean Volume of Distribution (V1/F) | Total apparent volume of distribution (Vss/F) is the total apparent volume in the body into which Fulvestrant distributes at equilibrium. Vss/F = V1/F + V2/F. V1/F is the volume of the 1st compartment and V2/F is the volume of the second compartment. V1/F only is presented here. The measure of variability presented is the inter-individual error. | Throughout the 12 month treatment period. | 
| PK: Mean Volume of Distribution (V2/F) . | Total apparent volume of distribution (Vss/F) is the total apparent volume in the body into which Fulvestrant distributes at equilibrium. Vss/F = V1/F + V2/F. V1/F is the volume of the 1st compartment and V2/F is the volume of the second compartment. V2/F only is presented here. The measure of variability presented is the inter-individual error. | Throughout the 12 month treatment period. | 
| Change in Breast Tanner Stage From Baseline to Month 12. | Change in breast Tanner stage from baseline to Month 12/last visit. Tanner stage (breast) is a score of range 1-5 where 1=no development and 5=adult breast | 6 month pre-treatment observation period (result at Month 0 considered as baseline) followed by 12 month treatment period (on treatment period). | 
| Change in Pubic Tanner Stage From Baseline to Month 12. | Change in pubic Tanner stage from baseline to Month 12/last visit. Tanner stage (pubic) is a score of range 1-5 where 1=no development and 5=adult pubic hair | 6 month pre-treatment observation period (result at Month 0 considered as baseline) followed by 12 month treatment period (on treatment period). | 
| Change in Predicted Adult Height (PAH) From Baseline to Month 12. | Change in PAH from baseline to Month 12/final visit for patients equal to or over 6 years of age. | 6 month pre-treatment observation period (result at Screening considered as baseline) followed by 12 month treatment period (on treatment period). | 
| Percentage of Patients With Gsα Mutation. | McCune-Albright Syndrome(MAS) is caused by an activating mutation in the gene coding for the stimulatory subunit of the G protein, Gsα. The altered Gsα causes autonomous activation of G-protein stimulated cAMP formation, which in the gonads, results in episodic uncontrolled sex steroid production and subsequent pubertal development. For patients who provided separate specific informed consent, the percentage of patients with a Gsα mutation at screening was assessed by molecular analysis. | Screening assessment (baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progressive Precocious Puberty, PPP, McCune-Albright Syndrome, MAS