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Effects of IAS in Men With Localized Biochemical Relapsed Prostate Cancer (IAS)

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ClinicalTrials.gov Identifier: NCT00223665
Recruitment Status : Completed
First Posted : September 22, 2005
Results First Posted : May 14, 2018
Last Update Posted : August 7, 2018
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Celestia Higano, University of Washington

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Prostate Cancer
Interventions Drug: Flutamide
Drug: Leuprolide Acetate
Enrollment 102
Recruitment Details The target population for this trial was men with localized prostate cancer who had a rising PSA after definitive therapy (radiation therapy, brachytherapy, or radical prostatectomy). Patients were enrolled from Jan 1997 through Sept 2006 at the University of Washington and the Seattle Cancer Care Alliance.
Pre-assignment Details  
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description

Intermittent Androgen Suppression in 9 month cycles:

  1. Flutamide, 250 mg by mouth 3 times daily for a total of two weeks
  2. Leuprolide Acetate, 7.5mg intramuscular injections every 4 weeks for a total of nine months
Period Title: Overall Study
Started 102
Completed 102
Not Completed 0
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Baseline Participants 102
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 102 participants
66
(60 to 81)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 102 participants
Female 0
Male 102
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 102 participants
American Indian or Alaska Native 0
Asian 1
Native Hawaiian or Other Pacific Islander 0
Black or African American 3
White 98
More than one race 0
Unknown or Not Reported 0
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 102 participants
102
 100.0%
1.Primary Outcome
Title Time to Androgen Independence of Serum Prostate-Specific Antigen (PSA)
Hide Description Monthly Prostate-Specific Antigen (PSA) testing to assess the point at which each patient's disease stops responding to Androgen Deprivation Therapy (ADT). Androgen Independence (AI), also know as Castrate Resistance (CR), was defined as 2 serial rises in PSA while on ADT with Testosterone levels <50 ng/dL.
Time Frame From date of first treatment until the date of development of CR, metastatic progression, or study withdrawal, whichever came first, assessed up to 16 years.
Hide Outcome Measure Data
Hide Analysis Population Description
62 subjects were evaluable for this outcome measure, defined as having completed first cycle of ADT (9 months), having a measurable treatment break afterwards, and having sufficient PSA measurements to assess androgen independence.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 62
Median (Full Range)
Unit of Measure: years
4.0
(0.5 to 8.6)
2.Primary Outcome
Title Effect of IAS on Overall Survival.
Hide Description Assessment of overall survival measured as median time from completion of first full cycle of IAS until date of death from any cause.
Time Frame From date of first treatment until the date of death or study withdrawal, whichever came first, assessed up to 16 years.
Hide Outcome Measure Data
Hide Analysis Population Description
62 subjects were evaluable for this outcome measure, defined as having completed first cycle of ADT (9 months), having a measurable treatment break afterwards, and having sufficient data to assess survival status.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 62
Median (Full Range)
Unit of Measure: years
6.6
(2.9 to 13.0)
3.Secondary Outcome
Title Change in Standardized Bone Mineral Density (BMD) of the Spine During IAS
Hide Description Dual-energy x-ray absorptiometry (DEXA) scans were performed prior to first cycle of ADT, after completion of the first cycle of ADT, and prior to the start of the second cycle of ADT. Bone Mineral Density (BMD) was a assessed in g/cm^2 as a indicator of bone health for each patient at each time point.
Time Frame From screening prior to first dose of ADT through the start of the second cycle of ADT.
Hide Outcome Measure Data
Hide Analysis Population Description
56 subjects were evaluable for this outcome measure, defined as meeting all of the following: having completed first cycle of ADT (9 months); no prior or concurrent use of bisphosphonates; a minimum of 3 DEXA scans: prior to cycle 1, after cycle 1, and prior to cycle 2.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 56
Measure Type: Number
Unit of Measure: Percent change in BMD
Post Cycle 1 versus Baseline -3.4
Pre Cycle 2 versus Post Cycle 1 1.4
4.Secondary Outcome
Title Change in Standardized Bone Mineral Density (BMD) of the Left Hip During IAS
Hide Description Dual-energy x-ray absorptiometry (DEXA) scans were performed prior to first cycle of ADT, after completion of the first cycle of ADT, and prior to the start of the second cycle of ADT. Bone Mineral Density (BMD) was a assessed in g/cm^2 as a indicator of bone health. Percent change was assess for each patient at each time point.
Time Frame From screening prior to first dose of ADT through the start of the second cycle of ADT.
Hide Outcome Measure Data
Hide Analysis Population Description
Out of 102 enrolled subjects, 56 were evaluable for this outcome measure, defined as having completed first cycle of ADT (9 months), no prior or concurrent use of bisphosphonates, and a minimum of 3 DEXA scans: prior to cycle 1, after cycle 1, and prior to cycle 2.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 56
Measure Type: Number
Unit of Measure: Percent change of BMD
Post Cycle 1 versus Baseline -1.2
Pre Cycle 2 versus Post Cycle 1 -0.2
5.Secondary Outcome
Title Development of Osteopenia (Bone Loss) During IAS
Hide Description Dual-energy x-ray absorptiometry (DEXA) scans were performed prior to first cycle of ADT, after completion of the first cycle of ADT, and prior to the start of the second cycle of ADT. Bone Mineral Density (BMD) was a assessed in g/cm^2 as a indicator of bone health for each patient at each time point. This measure was defined as the percentage of participants with normal BMD scores at baseline who developed Osteopenia after the first cycle of ADT.
Time Frame From screening prior to first dose of ADT through the start of the second cycle of ADT.
Hide Outcome Measure Data
Hide Analysis Population Description
38 subjects were evaluable for this outcome measure, defined as meeting all of the following: having completed first cycle of ADT (9 months); no prior or concurrent use of bisphosphonates; a minimum of 3 DEXA scans: prior to cycle 1, after cycle 1, and prior to cycle 2; having baseline DEXA BMD within normal range at both spine and left hip.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 38
Measure Type: Number
Unit of Measure: percent of participants
13.2
6.Secondary Outcome
Title Testosterone Levels During IAS
Hide Description Testosterone was measured at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having testosterone measurements at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: ng/ml
Baseline 406  (1.6)
Measurement at Month 3 0.28  (0.24)
Measurement at Month 9 0.20  (0.07)
Measurement at Month 12 2.45  (1.35)
7.Secondary Outcome
Title Estradiol Levels During First Cycle of IAS
Hide Description Estradiol was measured at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having estradiol measurements at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: pg/ml
Baseline 33.60  (17.29)
Measurement at Month 3 23.12  (6.56)
Measurement at Month 9 22.76  (5.75)
Measurement at Month 12 24.35  (6.46)
8.Secondary Outcome
Title Score on Spatial Ability Test (Block Design) During First Cycle of IAS
Hide Description Spatial Ability was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT. This assessment was based on the Wechsler Adult Intelligence Scale-Revised, Block Design sub-test and measures participants’ ability to analyze and construct abstract figures from their component parts. The test allows a time limit of 3 minutes per design, for a total of nine designs. Score is based on total number of designs completed (max 9, min 0).
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Combined Androgen Blockade
Hide Arm/Group Description:

Intermittent Hormone Therapy using Flutamide and Leuprolide acetate

Flutamide: 250mg three times a day by mouth

Leuprolide Acetate: 7.5mg once a month by intramuscular injection

Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: Number of correctly completed designs
Baseline 8.65  (0.81)
Score at Month 3 7.20  (1.21)
Score at Month 9 8.82  (0.53)
Score at Month 12 8.47  (1.06)
9.Secondary Outcome
Title Score on Spatial Ability Test (Mental Rotation) During First Cycle of IAS
Hide Description Spatial Ability (Mental Rotation) was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT. This assessment was based on the Vandenberg & Kuse (1978) Mental Rotation Test. Subjects are presented with line drawings of complex, three dimensional cubes on a computer screen. The subject must compare the two drawings and decide if they match. Score is based on number of correctly identified figures.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: Number of correctly identified figures
Baseline 16.12  (3.39)
Score at Month 3 13.00  (3.01)
Score at Month 9 16.52  (2.42)
Score at Month 12 15.53  (3.08)
10.Secondary Outcome
Title Score on Executive Function Testing (Stroop Task) During First Cycle of IAS
Hide Description Executive Function was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT. This assessment was based on the Stroop Color Word Interference Task. Subjects are asked to read 100 color words (red, green, blue), followed by identification of color blocks followed by reading the color of the ink and ignoring the word (e.g., the word ‘blue’ printed in green letters). Assessment was based on the amount of time needed to time to complete the assessment.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: minutes to complete the assessment
Baseline 51.00  (18.15)
Score at Month 3 55.52  (22.11)
Score at Month 9 47.58  (11.64)
Score at Month 12 48.82  (13.31)
11.Secondary Outcome
Title Score on Verbal Memory Testing (Proactive Interference) During First Cycle of IAS
Hide Description Verbal Memory was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT via the Proactive Interference (PI) task. The PI task involves participants listening to a list of 10 words from the same semantic category (e.g., articles of clothing), and then recalling as many of these words as possible.The procedure is repeated for a total of 4 trials. Assessment is based on the total number of words recalled.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: Number of correctly recalled words
Baseline 21.31  (5.50)
Score at Month 3 22.90  (5.03)
Score at Month 9 22.70  (5.33)
Score at Month 12 22.70  (4.33)
12.Secondary Outcome
Title Score on Visual Working Memory Test During First Cycle of IAS
Hide Description Visual Working Memory was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT. This task is based on the Subject Ordered Pointing Task (SOPT). The participant is shown a grid array of 10, 12 or 16 abstract designs and they must choose a new design with each refresh of the screen. Assessment is based on total number of errors.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: total number of errors
Baseline 13.22  (9.70)
Score at Month 3 15.66  (8.50)
Score at Month 9 12.35  (10.16)
Score at Month 12 14.00  (11.04)
13.Secondary Outcome
Title Score on Verbal Memory Testing (Story Recall) During First Cycle of IAS
Hide Description Verbal Memory was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT via Story Recall. This task is based on the well known Wechsler Memory Scale –Revised Logical Memory task. Participants listened to two brief narratives (stories) and were asked to recall as much as possible immediately after hearing each story and following a 20-minute delay. Assessment was based on number of correctly recalled pieces of information after a delay.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: number of correctly recalled data points
Baseline 35.06  (11.44)
Score at Month 3 37.86  (12.11)
Score at Month 9 39.38  (10.90)
Score at Month 12 41.16  (8.08)
14.Secondary Outcome
Title Score on Spatial Memory Testing During First Cycle of IAS
Hide Description Spatial Memory was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT using the Puget Sound Route Learning Test. This test measured the ability to navigate a short route within a room. Three trials were administered followed by three trials of a new route using pictures placed on the floor as landmarks. A delayed recall is administered after twenty minutes. Performance was assessed based on number of correctly recalled sequences after a delay.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: number of correctly recalled sequences
Baseline 19.50  (10.05)
Score at Month 3 22.00  (9.39)
Score at Month 9 23.76  (8.60)
Score at Month 12 24.12  (8.86)
15.Secondary Outcome
Title Score on Verbal Ability/Fluency Testing During First Cycle of IAS
Hide Description Verbal Ability/Fluency was assessed at baseline, and at Month 3, Month 9, and Month 12 after the start of the first cycle of ADT. Participants were asked to verbally generate as many words beginning with a particular letter (e.g. P) within a 60 second period. Two trials were administered with two different letters. The total number of words generated was recorded for each letter and summed and analyzed.
Time Frame Baseline, Month 3, Month 9, and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Sub-population of 20 evaluable patients, defined as having completed first cycle of ADT (9 months), having at least a 3 month treatment break afterwards, and having these neuro-psychological assessments at each of the listed time points.
Arm/Group Title Intermittent Androgen Suppression (IAS)
Hide Arm/Group Description:
Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: Number of words generated
Baseline 24.65  (7.11)
Score at Month 3 26.15  (9.14)
Score at Month 9 26.29  (7.44)
Score at Month 12 25.70  (8.29)
Time Frame Adverse Events were collected for each patient from the start of treatment until discontinuation from the study, an average of 16 years per patient.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Combined Androgen Blockade
Hide Arm/Group Description

Intermittent Hormone Therapy using Flutamide and Leuprolide acetate

Flutamide: 250mg three times a day by mouth

Leuprolide Acetate: 7.5mg once a month by intramuscular injection

All-Cause Mortality
Combined Androgen Blockade
Affected / at Risk (%)
Total   33/102 (32.35%)    
Show Serious Adverse Events Hide Serious Adverse Events
Combined Androgen Blockade
Affected / at Risk (%) # Events
Total   5/102 (4.90%)    
Cardiac disorders   
Atrioventricular node ablation   1/102 (0.98%)  1
Gastrointestinal disorders   
GI bleed   1/102 (0.98%)  3
Musculoskeletal and connective tissue disorders   
exacerbation of claudication   1/102 (0.98%)  1
left hip pain   1/102 (0.98%)  1
Nervous system disorders   
stroke   1/102 (0.98%)  1
Respiratory, thoracic and mediastinal disorders   
pnemonia   1/102 (0.98%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Combined Androgen Blockade
Affected / at Risk (%) # Events
Total   91/102 (89.22%)    
Cardiac disorders   
hypertension   6/102 (5.88%)  102
General disorders   
fatigue   9/102 (8.82%)  102
hot flashes   14/102 (13.73%)  102
weight gain   6/102 (5.88%)  102
Investigations   
hyperlipidemia   9/102 (8.82%)  102
Musculoskeletal and connective tissue disorders   
osteopenia   5/102 (4.90%)  102
pain, bone and muscle   6/102 (5.88%)  102
Psychiatric disorders   
depression   5/102 (4.90%)  102
Renal and urinary disorders   
urinary incontinence   12/102 (11.76%)  102
nocturia   15/102 (14.71%)  102
renal insufficiency   5/102 (4.90%)  102
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Celestia Higano, MD
Organization: University of Washington
Phone: 206-606-1187
EMail: mjcampbe@seattlecca.org
Layout table for additonal information
Responsible Party: Celestia Higano, University of Washington
ClinicalTrials.gov Identifier: NCT00223665     History of Changes
Other Study ID Numbers: 30296
973730AC06 ( Other Identifier: University of Washington, HSRC Approval # )
HSD 30296 ( Other Identifier: University of Washington, Human Subjects IRB # )
First Submitted: September 16, 2005
First Posted: September 22, 2005
Results First Submitted: November 25, 2017
Results First Posted: May 14, 2018
Last Update Posted: August 7, 2018