Faslodex in McCune Albright Syndrome (FMAS)

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Puberty, Precocious; McCune-Albright Syndrome	Drug: Fulvestrant	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	30 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	January 31, 2006
Actual Primary Completion Date :	December 8, 2009
Estimated Study Completion Date :	July 3, 2023

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1	Drug: Fulvestrant; intramuscular injection; Other Names: Faslodex; ZD9238

Outcome Measures

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Primary Outcome Measures :

1. Change in the Frequency of Annualised Days of Vaginal Bleeding [ Time Frame: 6 month pre-treatment observation period (baseline) followed by 12 month treatment period (on 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 .i.e. missing diary card days counted as bleeding days.

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 10 Years (Child)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Females less than or equal to 10 years of age (prior to 11th birthday)
• Diagnosis of McCune-Albright syndrome (MAS)
• Progressive precocious puberty (PPP) associated with MAS

Exclusion Criteria:

• Received any prior treatment for PPP associated with MAS with fulvestrant
• Abnormal platelet count or liver function tests
• Bleeding disorders
• Long term anticoagulation therapy
• Known hypersensitivity to any component of the study drug

Contacts and Locations

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Locations

United States, Alabama
Research Site
Birmingham, Alabama, United States, 35233
United States, Florida
Research Site
Miami, Florida, United States, 33136
United States, Kentucky
Research Site
Lexington, Kentucky, United States, 40536-0284
United States, Louisiana
Research Site
Baton Rouge, Louisiana, United States, 70808
United States, New York
Research Site
Bronx, New York, United States, 10467
United States, Pennsylvania
Research Site
Philadelphia, Pennsylvania, United States, 19104
United States, Utah
Research Site
Salt Lake City, Utah, United States, 84108
France
Research Site
Bordeaux, France
Research Site
Bron, France, 69677
Research Site
Paris Cedex 12, France, 75571
Germany
Research Site
Erlangen, Germany, 91054
Research Site
Osnabrück, Germany, 49082
Italy
Research Site
Torino, Italy, 10126
Russian Federation
Research Site
Moscow, Russian Federation, 117036
United Kingdom
Research Site
Liverpool, United Kingdom, L12 2AP
Research Site
London, United Kingdom, WC1N 3JH

Sponsors and Collaborators

AstraZeneca

Investigators

Study Director:	AstraZeneca Faslodex Medical Science Director, MD	AstraZeneca

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

CSR-D6992C00044.pdf 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sims EK, Garnett S, Guzman F, Paris F, Sultan C, Eugster EA; Fulvestrant McCune-Albright study group. Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome. Int J Pediatr Endocrinol. 2012 Sep 22;2012(1):26. doi: 10.1186/1687-9856-2012-26.

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT00278915 History of Changes
Other Study ID Numbers:	D6992C00044; EUDRACT Number: 2005-004893-29
First Posted:	January 19, 2006
Results First Posted:	July 19, 2011
Last Update Posted:	March 6, 2018
Last Verified:	March 2018

Keywords provided by AstraZeneca:

Progressive Precocious Puberty; PPP; McCune-Albright Syndrome; MAS

Additional relevant MeSH terms:

Fibrous Dysplasia, Polyostotic; Fibrous Dysplasia of Bone; Syndrome; Puberty, Precocious; Disease; Pathologic Processes; Gonadal Disorders; Endocrine System Diseases; Osteochondrodysplasias; Bone Diseases, Developmental	Bone Diseases; Musculoskeletal Diseases; Fulvestrant; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs