Clinical Trial Results:
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
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Summary
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EudraCT number |
2005-004893-26 |
Trial protocol |
GB ES DE IT |
Global end of trial date |
20 Jul 2023
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Results information
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Results version number |
v2(current) |
This version publication date |
20 Mar 2024
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First version publication date |
07 Jan 2024
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
D6992C00044
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00278915 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AstraZeneca Clinical study Information Center
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Sponsor organisation address |
One MedImmune Way, Gaithersburg, Maryland, United States, 20878
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Public contact |
Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Sep 2010
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Jul 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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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 McCune-Albright syndrome (MAS).
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Jan 2006
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Russian Federation: 4
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Country: Number of subjects enrolled |
United Kingdom: 6
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Country: Number of subjects enrolled |
United States: 9
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Worldwide total number of subjects |
30
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EEA total number of subjects |
11
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
30
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at study sites located in France, Germany, Italy, Russian Federation, United Kingdom, and the United States of America. | ||||||||||
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Pre-assignment
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Screening details |
A total of 30 participants were enrolled in this study. | ||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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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 drug-related toxicity requiring treatment discontinuation. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Fulvestrant
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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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 drug-related toxicity requiring treatment discontinuation.
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Baseline characteristics reporting groups
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Reporting group title |
Fulvestrant
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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 drug-related toxicity requiring treatment discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Fulvestrant
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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 drug-related toxicity requiring treatment discontinuation. | ||
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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 12-month 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 worst-case scenario calculation (ie, missing diary card days counted as bleeding days) are reported. The full-analysis set (FAS) population included participants who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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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 on-treatment 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 worst-case 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over a 6-month Treatment Period [3] | ||||||||
End point description |
Percentage of participants with baseline vaginal bleeding who experienced cessation of vaginal bleeding days over a 6-month treatment period based on a worst-case 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over the Whole 12-month Treatment Period [4] | ||||||||
End point description |
Percentage of participants with baseline vaginal bleeding who experienced cessation of vaginal bleeding days over a 12-month treatment period based on a worst-case 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Rate of Bone Age (BA) Advancement Over First 6-month Treatment Period Compared to Baseline [5] | ||||||||
End point description |
Change in rate of BA advancement over first 6-month treatment period compared to baseline (6 month pre-treatment 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 on-treatment 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 6 of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Rate of BA Advancement Over Second 6-month Treatment Period Compared to Baseline [6] | ||||||||
End point description |
Change in rate of BA advancement over second 6-month treatment period compared to baseline (6 month pre-treatment 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 on-treatment 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through second Month 6 of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Rate of BA Advancement Over the Whole 12-month Treatment Period Compared to Baseline [7] | ||||||||
End point description |
Change in rate of BA advancement over whole 12-month treatment period compared to baseline (6 month pre-treatment 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 on-treatment 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over First 6-month Treatment Period Compared to Baseline [8] | ||||||||
End point description |
Change in growth velocity (annualized growth velocity in cm/year) from the baseline (pre-treatment period) to first 6-month 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 6-month 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through first 6-month of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Growth Velocity (Annualised Growth Velocity in cm/year) Over Second 6-month Treatment Period Compared to Baseline [9] | ||||||||
End point description |
Change in growth velocity (annualized growth velocity in cm/year) from the baseline (pre-treatment period) to second 6-month 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 6-month 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through second 6-month treatment period (ie, through 12-month treatment period)
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Growth Velocity (Z-Score) Over the First 6-month Treatment Period Compared to Baseline [10] | ||||||||
End point description |
Change in growth velocity (Z-score) from baseline period to the first 6 months of treatment period is reported. The Z-score (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 gender-specific 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 6-month observational/retrospective period of the study. Z-score of 0 represents the population mean for growth velocity. For McCune-Albright Syndrome, Z-score below mean is a better outcome. The FAS population included participants who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through first 6-month treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Growth Velocity (Z-Score) Over the Second 6-month Treatment Period Compared to Baseline [11] | ||||||||
End point description |
Change in growth velocity (Z-score) from baseline period to the second 6 months of treatment period is reported. The Z-score (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 gender-specific 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 6-month observational/retrospective period of the study. Z-score of 0 represents the population mean for growth velocity. For McCune-Albright Syndrome, Z-score below mean is a better outcome. The FAS population included participants who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through second 6-month treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Growth Velocity (Z-Score) Over the Whole 12-month Treatment Period Compared to Baseline [12] | ||||||||
End point description |
Change in growth velocity (Z-score) from baseline period to 12 months of treatment period is reported. The Z-score (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 gender-specific 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 6-month observational/retrospective period of the study. Z-score of 0 represents the population mean for growth velocity. For McCune-Albright Syndrome, Z-score below mean is a better outcome. The FAS population included participants who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over Whole 12-month Treatment Period Compared to Baseline [13] | ||||||||
End point description |
Change in growth velocity (annualized growth velocity in cm/year) from the baseline (pre-treatment period) to the 12-month 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 6-month 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.
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End point type |
Primary
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End point timeframe |
Baseline (6 month pre-treatment observation period) through Month 12 of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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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 anterior-posterior 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 pre-treatment 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.
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End point type |
Primary
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End point timeframe |
Baseline (pre-treatment screening visit) and Month 6 of treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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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 pre-treatment 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.
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End point type |
Primary
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End point timeframe |
Baseline (pre-treatment screening visit) and Month 12 treatment period
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| 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. |
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| No statistical analyses for this end point | |||||||||
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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 pre-treatment 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 (pre-treatment 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 inter-individual error, not the Standard Error. The inter-individual 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 |
Post-dose: Weeks 1, 2, 3, and pre-dose: Week 4 of Month 1 for first 6 participants, then pre-dose 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 |
Post-dose: Weeks 1, 2, 3, and pre-dose: Week 4 of Month 1 for first 6 participants, then pre-dose 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 anterior-posterior 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 pre-treatment 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 (pre-treatment 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 inter-individual error, not the Standard Error. The inter-individual 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 |
Post-dose: Weeks 1, 2, 3, and pre-dose: Week 4 of Month 1 for first 6 participants, then pre-dose 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 anterior-posterior 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 protocol-defined 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 12-month 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 Follicle-stimulating 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 1-5 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 McCune-Albright Syndrome (MAS) Associated G Protein α-subunit (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 G-protein 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 1-5 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
|
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Timeframe for reporting adverse events |
Day 1 through 68.7 weeks (maximum observed duration)
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
|
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Reporting groups
|
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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 drug-related toxicity requiring treatment discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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 Five-Year 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. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| 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 time-point were too sparse to produce a meaningful summary, hence not reported. | |||
