Clinical Trial Results:
An Openlabel, NonComparative Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of FASLODEX™ (fulvestrant) in Girls with Progressive Precocious Puberty Associated with McCuneAlbright Syndrome
Summary


EudraCT number 
200500489326 
Trial protocol 
GB ES DE IT 
Global end of trial date 
20 Jul 2023

Results information


Results version number 
v2(current) 
This version publication date 
20 Mar 2024

First version publication date 
07 Jan 2024

Other versions 
v1 
Version creation reason 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
D6992C00044


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT00278915  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
AstraZeneca Clinical study Information Center


Sponsor organisation address 
One MedImmune Way, Gaithersburg, Maryland, United States, 20878


Public contact 
Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com


Scientific contact 
Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
Yes


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
03 Sep 2010


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
20 Jul 2023


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The primary objectives of the study included:
1. Safety component: The safety of study treatment will be evaluated by assessments of adverse events, withdrawals, laboratory data, ovarian volume as assessed by ultrasound, including the number of ovarian cysts and size of the largest cyst, and uterine volume.
2. Efficacy component: The efficacy of study treatment will be based on change in frequency of vaginal bleeding days, rate of increase in bone age, and growth rate.
3. Pharmacokinetics (PK) component: PK of fulvestrant in girls with progressive precocious puberty (PPP) associated with McCuneAlbright syndrome (MAS).


Protection of trial subjects 
The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
31 Jan 2006


Long term followup planned 
Yes


Long term followup rationale 
Safety  
Long term followup duration 
5 Years  
Independent data monitoring committee (IDMC) involvement? 
No


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
France: 5


Country: Number of subjects enrolled 
Germany: 3


Country: Number of subjects enrolled 
Italy: 3


Country: Number of subjects enrolled 
Russian Federation: 4


Country: Number of subjects enrolled 
United Kingdom: 6


Country: Number of subjects enrolled 
United States: 9


Worldwide total number of subjects 
30


EEA total number of subjects 
11


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
30


Adolescents (1217 years) 
0


Adults (1864 years) 
0


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
The study was conducted at study sites located in France, Germany, Italy, Russian Federation, United Kingdom, and the United States of America.  
Preassignment


Screening details 
A total of 30 participants were enrolled in this study.  
Period 1


Period 1 title 
Overall Study (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Not applicable


Blinding used 
Not blinded  
Arms


Arm title

Fulvestrant  
Arm description 
Participants received intramuscular injection of fulvestrant 2 mg/kg or 4 mg/kg (First 10 participants were dosed at 2 mg/kg then increased to 4 mg/kg. All subsequent participants were dosed at 4 mg/kg) into the buttock or thigh monthly for 12 months or until the participant demonstrates lack of efficacy based upon one or more of the primary endpoints or experiences a serious drugrelated toxicity requiring treatment discontinuation.  
Arm type 
Experimental  
Investigational medicinal product name 
Fulvestrant


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Solution for injection


Routes of administration 
Intramuscular use


Dosage and administration details 
Participants received intramuscular injection of fulvestrant 2 mg/kg or 4 mg/kg (First 10 participants were dosed at 2 mg/kg then increased to 4 mg/kg. All subsequent participants were dosed at 4 mg/kg) into the buttock or thigh monthly for 12 months or until the participant demonstrates lack of efficacy based upon one or more of the primary endpoints or experiences a serious drugrelated toxicity requiring treatment discontinuation.





Baseline characteristics reporting groups


Reporting group title 
Fulvestrant


Reporting group description 
Participants received intramuscular injection of fulvestrant 2 mg/kg or 4 mg/kg (First 10 participants were dosed at 2 mg/kg then increased to 4 mg/kg. All subsequent participants were dosed at 4 mg/kg) into the buttock or thigh monthly for 12 months or until the participant demonstrates lack of efficacy based upon one or more of the primary endpoints or experiences a serious drugrelated toxicity requiring treatment discontinuation.  



End points reporting groups


Reporting group title 
Fulvestrant


Reporting group description 
Participants received intramuscular injection of fulvestrant 2 mg/kg or 4 mg/kg (First 10 participants were dosed at 2 mg/kg then increased to 4 mg/kg. All subsequent participants were dosed at 4 mg/kg) into the buttock or thigh monthly for 12 months or until the participant demonstrates lack of efficacy based upon one or more of the primary endpoints or experiences a serious drugrelated toxicity requiring treatment discontinuation. 


End point title 
Change in Frequency of Annualised Days of Vaginal Bleeding on Treatment Compared to Baseline ^{[1]}  
End point description 
Vaginal bleeding days are defined as the number of days in which vaginal bleeding, (including spotting) occurred. In order to annualise, a 12 month period is defined as 360 days and a 6 month period is defined as 180 days. Frequency of annualised vaginal bleeding days = [(number of vaginal bleeding days)/(total number of days of the time interval under consideration)] multiplied by 360. Change in frequency is equal to the on treatment frequency minus the baseline frequency. Diary cards will capture days of vaginal bleeding during the 12month treatment period. 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 worstcase scenario calculation (ie, missing diary card days counted as bleeding days) are reported. The fullanalysis set (FAS) population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 treatment period


Notes [1]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Percentage of Participants With Baseline Vaginal Bleeding Who Experienced ≥ 50% Reduction in the Number of Vaginal Bleeding Days on Treatment Compared to Baseline ^{[2]}  
End point description 
The percentage change in frequency is defined as 100% times the difference (the ontreatment period frequency minus the baseline period frequency), divided by the baseline period frequency. The percentage of participants with baseline vaginal bleeding days who experienced ≥ 50% reduction in the number of vaginal bleeding days during the 12 month treatment period compared to the 6 month baseline period based on a worstcase approach (ie, missing diary card days counted as bleeding days) are reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who had bleeding during the 6 month baseline period.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 treatment period


Notes [2]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over a 6month Treatment Period ^{[3]}  
End point description 
Percentage of participants with baseline vaginal bleeding who experienced cessation of vaginal bleeding days over a 6month treatment period based on a worstcase approach (ie, missing diary card days counted as bleeding days) are reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who had bleeding during the 6 month baseline period.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 treatment period


Notes [3]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over the Whole 12month Treatment Period ^{[4]}  
End point description 
Percentage of participants with baseline vaginal bleeding who experienced cessation of vaginal bleeding days over a 12month treatment period based on a worstcase approach (ie, missing diary card days counted as bleeding days) are reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who had bleeding during the 6 month baseline period.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 treatment period


Notes [4]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Rate of Bone Age (BA) Advancement Over First 6month Treatment Period Compared to Baseline ^{[5]}  
End point description 
Change in rate of BA advancement over first 6month treatment period compared to baseline (6 month pretreatment observation period) is reported. Increase in BA is defined as BA (expressed as fractional years) at end of time period minus BA at beginning of time period (unit: years). Rate of increase in BA for a particular time interval is increase in BA during this time interval adjusted (ie, normalized) for the length of this time interval. Rate of BA advancement is change in BA (years) divided by change in chronological age (CA) (years). Change in rate of increase in BA from baseline period to ontreatment period is defined as increase in BA divided by change in CA (in fractional years) between BA radiograph dates. It is calculated as [(BA6 – BA0)/(CA6 – CA0)] – [(BA0 – BA*)/(CA0 – CA*)], where 6, 0, * stands for first Month 6 Visit, Month 0 Visit, and the 6 month retrospective visit, respectively. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 6 of treatment period


Notes [5]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Rate of BA Advancement Over Second 6month Treatment Period Compared to Baseline ^{[6]}  
End point description 
Change in rate of BA advancement over second 6month treatment period compared to baseline (6 month pretreatment observation period) is reported. Increase in BA is defined as BA (expressed as fractional years) at end of time period minus BA at beginning of time period (unit: years). Rate of increase in BA for a particular time interval is increase in BA during this time interval adjusted (ie, normalized) for the length of this time interval. Rate of BA advancement is change in BA (years) divided by change in CA (years). Change in rate of increase in BA from baseline period to ontreatment period is defined as increase in BA divided by change in CA (in fractional years) between the BA radiograph dates. It is calculated as [(BA6 – BA0)/(CA6 – CA0)] – [(BA0 – BA*)/(CA0 – CA*)], where 6, 0, * stands for second Month 6 Visit, Month 0 Visit, and the 6 month retrospective visit, respectively. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through second Month 6 of treatment period


Notes [6]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Rate of BA Advancement Over the Whole 12month Treatment Period Compared to Baseline ^{[7]}  
End point description 
Change in rate of BA advancement over whole 12month treatment period compared to baseline (6 month pretreatment observation period) is reported. Increase in BA is defined as BA (expressed as fractional years) at end of time period minus BA at beginning of time period (unit: years). Rate of increase in BA for a particular time interval is increase in BA during this time interval adjusted (ie, normalized) for the length of this time interval. Rate of BA advancement is change in BA (years) divided by change in CA (years). Change in rate of increase in BA from baseline period to ontreatment period is defined as increase in BA divided by change in CA (in fractional years) between the BA radiograph dates. It is calculated as [(BA12 – BA0) / (CA12 – CA0)] – [(BA0 – BA*) / (CA0 – CA*)], where 12, 0, * stands for Month 12 Visit, Month 0 Visit, and the 6 month retrospective visit, respectively. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 of treatment period


Notes [7]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over First 6month Treatment Period Compared to Baseline ^{[8]}  
End point description 
Change in growth velocity (annualized growth velocity in cm/year) from the baseline (pretreatment period) to first 6month treatment period is reported. 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). Baseline growth velocity was calculated from 6month observational/retrospective period of the study. Change in growth velocity was calculated as growth velocity on treatment minus change in growth velocity during baseline. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through first 6month of treatment period


Notes [8]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Growth Velocity (Annualised Growth Velocity in cm/year) Over Second 6month Treatment Period Compared to Baseline ^{[9]}  
End point description 
Change in growth velocity (annualized growth velocity in cm/year) from the baseline (pretreatment period) to second 6month treatment period is reported. 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). Baseline growth velocity was calculated from 6month observational/retrospective period of the study. Change in growth velocity was calculated as growth velocity on treatment minus change in growth velocity during baseline. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through second 6month treatment period (ie, through 12month treatment period)


Notes [9]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Growth Velocity (ZScore) Over the First 6month Treatment Period Compared to Baseline ^{[10]}  
End point description 
Change in growth velocity (Zscore) from baseline period to the first 6 months of treatment period is reported. The Zscore (also known as Standard Deviation Score[SDS]) is defined as [(growth velocity from the previous visit to the current visit minus mean growth velocity) divided by standard deviation (SD)], where the mean and SD are the age and genderspecific statistics for growth velocity from the National Center for Health Statistics, Fels study and age is the age at the current visit. Baseline growth velocity was calculated from 6month observational/retrospective period of the study. Zscore of 0 represents the population mean for growth velocity. For McCuneAlbright Syndrome, Zscore below mean is a better outcome. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through first 6month treatment period


Notes [10]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Growth Velocity (ZScore) Over the Second 6month Treatment Period Compared to Baseline ^{[11]}  
End point description 
Change in growth velocity (Zscore) from baseline period to the second 6 months of treatment period is reported. The Zscore (also known as SDS) is defined as [(growth velocity from the previous visit to the current visit minus mean growth velocity) divided by SD], where the mean and SD are the age and genderspecific statistics for growth velocity from the National Center for Health Statistics, Fels study and age is the age at the current visit. Baseline growth velocity was calculated from 6month observational/retrospective period of the study. Zscore of 0 represents the population mean for growth velocity. For McCuneAlbright Syndrome, Zscore below mean is a better outcome. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through second 6month treatment period


Notes [11]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Growth Velocity (ZScore) Over the Whole 12month Treatment Period Compared to Baseline ^{[12]}  
End point description 
Change in growth velocity (Zscore) from baseline period to 12 months of treatment period is reported. The Zscore (also known as SDS) is defined as [(growth velocity from the previous visit to the current visit minus mean growth velocity) divided by SD)], where the mean and SD are the age and genderspecific statistics for growth velocity from the National Center for Health Statistics, Fels study and age is the age at the current visit. Baseline growth velocity was calculated from 6month observational/retrospective period of the study. Zscore of 0 represents the population mean for growth velocity. For McCuneAlbright Syndrome, Zscore below mean is a better outcome. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 of treatment period


Notes [12]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over Whole 12month Treatment Period Compared to Baseline ^{[13]}  
End point description 
Change in growth velocity (annualized growth velocity in cm/year) from the baseline (pretreatment period) to the 12month treatment period is reported. 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). Baseline growth velocity was calculated from 6month observational/retrospective period of the study. Change in growth velocity was calculated as growth velocity on treatment minus change in growth velocity during baseline. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Baseline (6 month pretreatment observation period) through Month 12 of treatment period


Notes [13]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Mean Ovarian Volume From Baseline to Month 6 as Assessed by Ultrasound ^{[14]}  
End point description 
The mean ovarian volume was the average of both ovaries. Average volume was calculated as 0.5 multiplied by (volume of left ovary plus volume of right ovary) if both volumes were calculated; otherwise, average ovarian volume was considered missing. The volume of each ovary was calculated via ultrasound using the formula: 0.5 multiplied by longitudinal dimension multiplied by anteriorposterior dimension multiplied by transverse dimension. Change in mean ovarian volume from baseline to Month 6 was calculated as Month 6 mean volume minus Screening Visit mean volume. Baseline (screening visit) is the pretreatment baseline visit. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants with data at both time points.


End point type 
Primary


End point timeframe 
Baseline (pretreatment screening visit) and Month 6 of treatment period


Notes [14]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Uterine Volume From Baseline to Month 12/Final Visit as Assessed by Ultrasound ^{[15]}  
End point description 
Uterine volume was calculated via ultrasound using the formula: 0.5 multiplied by (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. Change in uterine volume from baseline to Month 12/final visit was calculated as End of Study volume (by ultrasound) minus Screening Visit volume (by ultrasound). Baseline (screening visit) is the pretreatment baseline visit. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants with data at both time points.


End point type 
Primary


End point timeframe 
Baseline (pretreatment screening visit) and Month 12 treatment period


Notes [15]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Uterine Volume From Baseline to Month 6 as Assessed by Ultrasound ^{[16]}  
End point description 
Uterine volume was calculated via ultrasound using the formula: 0.5 multiplied by (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. Change in uterine volume from baseline to Month 6 was calculated as Month 6 volume (by ultrasound) minus screening visit volume (by ultrasound). Baseline (screening visit) is the pretreatment baseline visit. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants with data at both time points.


End point type 
Primary


End point timeframe 
Baseline (pretreatment baseline visit) and Month 6 of treatment period


Notes [16]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Uterine Volume From Month 6 to Month 12/Final Visit as Assessed by Ultrasound ^{[17]}  
End point description 
Uterine volume was calculated via ultrasound using the formula: 0.5 multiplied by (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. Change in uterine volume from Month 6 to Month 12/final visit was calculated as Month 12/finial visit volume (by ultrasound) minus Month 6 volume (by ultrasound). The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants with data at both time points.


End point type 
Primary


End point timeframe 
At Month 6 and Month 12/final visit treatment period


Notes [17]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Mean Volume of Distribution (V1/F) of Fulvestrant ^{[18]}  
End point description 
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 first compartment and V2/F is the volume of the second compartment. V1/F of fulvestrant is reported. The measure of variability presented is the interindividual error, not the Standard Error. The interindividual error = 0.492. The arbitrary number 99999 denotes that the Standard Error was not calculated. Population PK analysis set included all participants who received at least 1 dose of study drug and have evaluable PK data.


End point type 
Primary


End point timeframe 
Postdose: Weeks 1, 2, 3, and predose: Week 4 of Month 1 for first 6 participants, then predose steady state samples on 2 occasions between Month 6 and 12 with at least 1 month in between wherein first sample drawn at least 30 days following sixth dose


Notes [18]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Mean Clearance of Fulvestrant ^{[19]}  
End point description 
Mean clearance of fulvestrant is reported. Population pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of study drug and have evaluable PK data.


End point type 
Primary


End point timeframe 
Postdose: Weeks 1, 2, 3, and predose: Week 4 of Month 1 for first 6 participants, then predose steady state samples on 2 occasions between Month 6 and 12 with at least 1 month in between wherein first sample drawn at least 30 days following sixth dose


Notes [19]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Mean Ovarian Volume From Baseline to Month 12/Final Visit as Assessed by Ultrasound ^{[20]}  
End point description 
The mean ovarian volume was the average of both ovaries. Average ovarian volume was calculated as 0.5 multiplied by (volume of left ovary plus volume of right ovary) if both volumes were calculated; otherwise, average ovarian volume was considered missing. The volume of each ovary was calculated via ultrasound using the formula: 0.5 multiplied by longitudinal dimension multiplied by anteriorposterior dimension multiplied by transverse dimension. Change in mean ovarian volume from baseline to the end of the study was calculated as end of study mean volume minus screening visit mean volume. Baseline (screening visit) is the pretreatment baseline visit. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants with data at both time points.


End point type 
Primary


End point timeframe 
Baseline (pretreatment baseline visit) and Month 12/final visit treatment period


Notes [20]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Mean Volume of Distribution (V2/F) of Fulvestrant ^{[21]}  
End point description 
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 first compartment and V2/F is the volume of the second compartment. V2/F of fulvestrant is reported. The measure of variability presented is the interindividual error, not the Standard Error. The interindividual error = 0.296. The arbitrary number 99999 denotes that the Standard Error was not calculated. Population PK analysis set included all participants who received at least 1 dose of study drug and have evaluable PK data.


End point type 
Primary


End point timeframe 
Postdose: Weeks 1, 2, 3, and predose: Week 4 of Month 1 for first 6 participants, then predose steady state samples on 2 occasions between Month 6 and 12 with at least 1 month in between wherein first sample drawn at least 30 days following sixth dose


Notes [21]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change Mean in Ovarian Volume From Month 6 to Month 12/Final Visit as Assessed by Ultrasound ^{[22]}  
End point description 
The mean ovarian volume was the average of both ovaries. Average volume was calculated as 0.5 multiplied by (volume of left ovary plus volume of right ovary) if both volumes were calculated; otherwise, average ovarian volume was considered missing. The volume of each ovary was calculated via ultrasound using the formula: 0.5 multiplied by longitudinal dimension multiplied by anteriorposterior dimension multiplied by transverse dimension. Change in mean ovarian volume from Month 6 to Month 12/final visit was calculated as Month 12/final visit mean volume minus Month 6 mean volume. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants with data at both time points.


End point type 
Primary


End point timeframe 
At Month 6 and Month 12/final visit treatment period


Notes [22]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs ^{[23]}  
End point description 
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Clinical laboratory parameter analysis included hematology and clinical chemistry. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Day 1 through 68.7 weeks (maximum observed duration)


Notes [23]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) ^{[24]}  
End point description 
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Day 1 through 68.7 weeks (maximum observed duration)


Notes [24]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Number of Participants With Compliance to Study Treatment ^{[25]}  
End point description 
Number of participants with compliance to study treatment are reported. Treatment compliance was ensured at each treatment visit whether each participant received all protocoldefined injections up until the point they either withdrew from the study or completed the main study period. Compliance with study treatment for each participant for the 12month treatment period was calculated as total number of injections divided by number of visits between first injection (month 0) and last injection (at month 11). The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Day 1 through Month 12 of treatment period


Notes [25]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Hormone Assay: Serum Testosterone Level ^{[26]}  
End point description 
Serum testosterone level at Month 12 (final visit) is reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who were evaluable at the specified time point.


End point type 
Primary


End point timeframe 
Month 12 (final visit) of treatment period


Notes [26]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Hormone Assay: Serum Folliclestimulating Hormone (FSH) Level ^{[27]}  
End point description 
Serum FSH level collected at Month 12 (final visit) is reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who were evaluable at the specified time point.


End point type 
Primary


End point timeframe 
Month 12 (final visit) of treatment period


Notes [27]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Number of Participants With Withdrawals from Study Treatment due to TEAE ^{[28]}  
End point description 
Number of participants with withdrawals from study treatment due to TEAE are reported. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Primary


End point timeframe 
Day 1 through 68.7 weeks (maximum observed duration)


Notes [28]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Hormone Assay: Serum Oestradiol Level ^{[29]}  
End point description 
Serum oestradiol level at Month 12 (final visit) is reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who were evaluable at the specified time point.


End point type 
Primary


End point timeframe 
Month 12 (final visit) of treatment period


Notes [29]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Hormone Assay: Serum Luteinizing Hormone (LH) Level ^{[30]}  
End point description 
Serum LH level collected at Month 12 (final visit) is reported. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who were evaluable at the specified time point.


End point type 
Primary


End point timeframe 
Month 12 (final visit) of treatment period


Notes [30]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. 



No statistical analyses for this end point 


End point title 
Change in Tanner Stage of Breast From Baseline to Month 12/Final Visit  
End point description 
Change in Tanner stage (measure of pubertal progression) of breast from baseline to Month 12/last visit is reported. Tanner stage (breast) is a score of range 15 where 1=no development and 5=adult breast. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Secondary


End point timeframe 
From Baseline (Month 0) through Month 12 treatment period




No statistical analyses for this end point 


End point title 
Percentage of Participants With McCuneAlbright Syndrome (MAS) Associated G Protein αsubunit (Gsα) Mutation  
End point description 
The 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 Gprotein stimulated cAMP formation, which in the gonads, results in episodic uncontrolled sex steroid production and subsequent pubertal development. For participants who provided separate specific informed consent, the percentage of participants with a Gsα mutation at screening was assessed by molecular analysis of peripheral blood. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Secondary


End point timeframe 
Baseline (screening)




No statistical analyses for this end point 


End point title 
Change in Tanner Stage of Pubic Hair From Baseline to Month 12/Final Visit  
End point description 
Change in Tanner stage (measure of pubertal progression) of pubic hair from baseline to Month 12/final visit is reported. Tanner stage (pubic hair) is a score of range 15 where 1=no development and 5=adult pubic hair. The FAS population included participants who received at least 1 dose of study drug.


End point type 
Secondary


End point timeframe 
From Baseline (Month 0) through Month 12 treatment period




No statistical analyses for this end point 


End point title 
Change in Predicted Adult Height (PAH) From Baseline to Month 12/Final Visit  
End point description 
Change in PAH for children over age 6 is reported. Bone age radiographs were collected retrospectively. PAH equals the current height divided by a factor (the fraction of final adult height) based on current bone age (central read) and current bone age relative to chronological age, classified as retarded, average or advanced. Retarded is defined as current bone age (years) < chronological age (years) minus 1; advanced is defined as current bone age (years) > chronological age (years) plus 1; otherwise, bone age is classified as average. The PAH was summarized using the Bayley and Pinneau method. The FAS population included participants who received at least 1 dose of study drug. Here, number of subjects analyzed denotes those participants who were analyzed for this endpoint.


End point type 
Secondary


End point timeframe 
From Baseline (screening visit) through Month 12 treatment period




No statistical analyses for this end point 


Adverse events information


Timeframe for reporting adverse events 
Day 1 through 68.7 weeks (maximum observed duration)


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
12.1


Reporting groups


Reporting group title 
Fulvestrant


Reporting group description 
Participants received intramuscular injection of fulvestrant 2 mg/kg or 4 mg/kg (First 10 participants were dosed at 2 mg/kg then increased to 4 mg/kg. All subsequent participants were dosed at 4 mg/kg) into the buttock or thigh monthly for 12 months or until the participant demonstrates lack of efficacy based upon one or more of the primary endpoints or experiences a serious drugrelated toxicity requiring treatment discontinuation.  


Frequency threshold for reporting nonserious adverse events: 5%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

06 Mar 2008 
Various sections throughout the original Clinical Study Protocol (CSP): Text revised to reflect the fact that separate consent was not required for the FiveYear Safety Surveillance period. Text revised to clarify that first month blood samples were only required for the first 6 participants. The collection period for steady state samples was revised to include Month 10, 11 and 12. Text in Sections 3.4.1.1 and 3.4.2 revised to clarify syringes provided in the Unites States and Rest of World. Text in Section 3.4.2 also revised to indicate that injection could be given in the buttock or thigh. Section 4.2, Screening and demographic measurements; text removed to make it clear that retrospective data was available for some participants prior to written informed consent. Various sections throughout the original CSP: Text revised for to clarify that full physical exams, including Tanner stage, were performed at Month 0, 3, 6 and 12 only. Height and weight were collected at each study visit. Text added to indicate that for Months 0 to 12, radiographs were read both locally and centrally. In the extension period only, local radiographs were collected. Additional text added to indicate that a telephone visit or participant office visit was required 60 days following the last injection of study drug to collect any post treatment AEs. Text was added to clarify that the genetic specimens will be analyzed at an independent institute. Section 5, Data management: text edited to include the possibility that case report forms would be sent to an AstraZeneca designee. 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
Data for exploration on body weight and race effect on fulvestrant PK is not available due to small sample size. Data for number and size of ovarian cysts at different timepoint were too sparse to produce a meaningful summary, hence not reported. 