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Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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Official Title

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:
https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. "Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

Participants will receive intramuscular injection of fulvestrant 2 mg/kg or 4 mg/kg (First 10 participants will be dosed at 2 mg/kg then increased to 4 mg/kg. All subsequent participants will be 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.

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 (PPP) (early puberty) in girls with McCune-Albright syndrome (MAS)

Faslodex in McCune-Albright Syndrome

CTIS Number

EudraCT Number

NCT ID

Patient Level Data

Therapeutic Area

Participants will receive intramuscular injection of fulvestrant as stated in arm description.

Research Site

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

Vaginal bleeding days are defined as the number of days in which vaginal bleeding, (including spotting) occurred. In order to annualize, a 12-month period is defined as 360 days and a 6-month period is defined as 180 days. Frequency of annualized 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 annualized 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 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.

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.

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.

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, * stand for first Month 6 Visit, Month 0 Visit, and the 6-month retrospective visit, respectively.

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, * stand for second Month 6 Visit, Month 0 Visit, and the 6-month retrospective visit, respectively.

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, * stand for Month 12 Visit, Month 0 Visit, and the 6-month retrospective visit, respectively.

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.

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.

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.

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.

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.

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.

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.

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).

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 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 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 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.

Mean clearance of fulvestrant is reported.

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.

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.

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.

Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Clinical laboratory parameter analysis included hematology and clinical chemistry.

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).

Number of participants with withdrawals from study treatment due to TEAE are reported.

Serum oestradiol level at Month 12 (final visit) is reported.

Serum LH level collected at Month 12 (final visit) is reported.

Serum FSH level collected at Month 12 (final visit) is reported.

Serum testosterone level at Month 12 (final visit) is reported.

Age Continuous

Sex: Female, Male

Race (NIH/OMB)

Ethnicity (NIH/OMB)

The full-analysis set (FAS) population included participants who received at least 1 dose of study drug.

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.

Change in Frequency of Annualized Days of Vaginal Bleeding on Treatment Compared to Baseline

The FAS population included participants who received at least 1 dose of study drug. Here, number of participants analyzed denotes those participants who had bleeding during the 6 month baseline period.

Percentage of Participants With Baseline Vaginal Bleeding Who Experienced ≥ 50% Reduction in the Number of Vaginal Bleeding Days on Treatment Compared to Baseline

The FAS population included participants who received at least 1 dose of study drug. Here, number of participants analyzed denotes those participants who had bleeding during the 6-month baseline period.

Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over a 6-month Treatment Period

Percentage of Participants With Baseline Vaginal Bleeding Who Experienced Cessation of Vaginal Bleeding Over the Whole 12-month Treatment Period

The FAS population included participants who received at least 1 dose of study drug.

Change in Rate of Bone Age (BA) Advancement Over First 6-month Treatment Period Compared to Baseline

The FAS population included participants who received at least 1 dose of study drug. Here, number of participants analyzed denotes those participants who were evaluable at the specified time point.

Change in Rate of BA Advancement Over Second 6-month Treatment Period Compared to Baseline

Change in Rate of BA Advancement Over the Whole 12-month Treatment Period Compared to Baseline

Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over First 6-month Treatment Period Compared to Baseline

Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over Second 6-month Treatment Period Compared to Baseline

Change in Growth Velocity (Annualized Growth Velocity in cm/year) Over Whole 12-month Treatment Period Compared to Baseline

Change in Growth Velocity (Z-score) Over the First 6-month Treatment Period Compared to Baseline

Change in Growth Velocity (Z-score) Over the Second 6-month Treatment Period Compared to Baseline

Change in Growth Velocity (Z-score) Over the Whole 12-month Treatment Period Compared to Baseline

The FAS population included participants who received at least 1 dose of study drug. Here, number of participants analyzed denotes those participants with data at both time points.

Change in Uterine Volume From Baseline to Month 6 as Assessed by Ultrasound

Change in Uterine Volume From Month 6 to Month 12/Final Visit as Assessed by Ultrasound

Change in Uterine Volume From Baseline to Month 12/Final Visit as Assessed by Ultrasound

Change in Mean Ovarian Volume From Baseline to Month 6 as Assessed by Ultrasound

Change Mean in Ovarian Volume From Month 6 to Month 12/Final Visit as Assessed by Ultrasound

Change in Mean Ovarian Volume From Baseline to Month 12/Final Visit as Assessed by Ultrasound

Population pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of study drug and have evaluable PK data.

Mean Clearance of Fulvestrant

Population PK analysis set included all participants who received at least 1 dose of study drug and have evaluable PK data.

Mean Volume of Distribution (V1/F) of Fulvestrant

Mean Volume of Distribution (V2/F) of Fulvestrant

Any TEAEs

Any TESAEs

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Anemia

Vitamin D Deficiency

Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

Number of Participants With Compliance to Study Treatment

Number of Participants With Withdrawals from Study Treatment due to TEAE

he FAS population included participants who received at least 1 dose of study drug. Here, number of participants analyzed denotes those participants who were evaluable at the specified time point.

Hormone Assay: Serum Oestradiol Level

Hormone Assay: Serum Luteinizing Hormone (LH) Level

Hormone Assay: Serum Follicle-stimulating Hormone (FSH) Level

Hormone Assay: Serum Testosterone Level

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.

Change in Tanner Stage of Breast From Baseline to Month 12/Final Visit

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.

Change in Tanner Stage of Pubic Hair From Baseline to Month 12/Final Visit

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 participants analyzed denotes those participants who were analyzed for this endpoint.

Change in Predicted Adult Height (PAH) From Baseline to Month 12/Final Visit

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 cyclic adenosine monophosphate (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.

Percentage of Participants With McCune-Albright Syndrome (MAS) Associated G Protein α-subunit (Gsα) Mutation

Overall Study

A total of 30 participants were enrolled in this study.

Faslodex in McCune-Albright Syndrome - FMAS

Official Title

Medical condition

Phase

Healthy volunteers

Study drug

Sex

Actual Enrollment

Study type

Age

Date

Study design

Verification:

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Documents available

CSR-D6992C00044.pdf

CSR Synopsis Redacted

Trial Results Summaries

Contacts

Contact

Investigators

Principal Investigator