A Study of the Effect of Enantone LP 11.25 mg (Leuprorelin) on the Histological Progression of Indolent Prostate Cancer

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02085252
• Collaborator: (none)
• Enrollment: 116
• Locations: 2
• Arms: 2
• Actual Duration (Months): 41.2
• Patients Per Site: 58
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this study is to assess two treatment strategies (leuprorelin treatment and active surveillance without androgen deprivation) for indolent prostate cancer and to compare their therapeutic benefit for management of patients with low-risk, localized prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Leuprorelin; Drug: Bicalutamide	Phase 3

Detailed Description

The drug being tested in this study is called leuprorelin. Leuprorelin is being tested to treat people who have prostate cancer. Study assessments will include adverse events, prostatic-specific antigen (PSA) levels, and prostate biopsies.

The study will enroll approximately 120 patients. Participants will be randomly assigned (by chance, like flipping a coin) to a treatment group that will receive leuprorelin 11.25 mg (as one injection) or to an untreated observation group. Patients in the leuprorelin group will also receive bicalutamide 50 mg, a non-steroidal antiandrogen, once daily for 15 days to prevent a flare-up.

This multi-center trial will be conducted in France. The overall time to participate in this study is 12 months. After the screening visit, participants will make 6 visits to the clinic.

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Phase III Study to Assess the Impact of Transient Androgenic Deprivation With Enantone LP 11.25 Mg (Leuprorelin) on the Histological Progression of Indolent Prostate Cancer
• Actual Study Start Date: Jun 3, 2013
• Actual Primary Completion Date: Nov 8, 2016
• Actual Study Completion Date: Nov 8, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Leuprorelin 11.25 mg Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Drug: Leuprorelin; Solution for injection; Other Names: Enantone ® ; Drug: Bicalutamide; Bicalutamide tablets; Other Names: Casodex ®
No Intervention: Active surveillance Active surveillance is close medical monitoring of prostate cancer for any changes.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Negative Biopsies at Month 12 [Month 12]

   Staging biopsy of at least 12 cores were sampled and analyzed according to a centralized biopsy procedure which confirm the results of the first biopsy [presence of positive cores, the absence of core with tumor length > 3 millimeters (mm), and absence Grade 4 cells (Gleason score < 7)]. The Gleason score grades prostate cancer tissue, based on its appearance under a microscope. Scores range from 2 to 10, with a higher score meaning that the cancer tissue is more likely to spread.

Secondary Outcome Measures

1. Number of Participants With Gleason Score ≥ 7 [Month 12]

   Gleason score grades prostate cancer tissue, based on its appearance under a microscope. Scores range from 2 to 10, with a higher score meaning that the cancer tissue is more likely to spread.

2. Change From Baseline in the International Prostate Symptom Score (I-PSS) Total Symptom (S) Score [Baseline and Months 3, 6, 9 and 12]

   The I-PSS is an 8-question tool used to measure prostate symptoms (≤7: mildly symptomatic; 8-19 moderately symptomatic; 20-35 severely symptomatic). The first 7 symptom questions answered on a scale of 0 (never) to 5 (almost always) are used to determine the I-PSS Total S Score for a total possible score of 0 to 35. The 8th question is quality of life and is not reported here. A negative change from baseline indicates improvement. An Analysis of Covariance (ANCOVA) model fitted with baseline I-PSS total score and age as covariates was used for analysis.

3. Prostatic Volume as a Measure of Tumor Radiologic Progression Using Dynamic Magnetic Resonance Imaging (MRI) [Baseline and Month 12]

   MRI is an imaging technique used to investigate the anatomy and function of the body. Measurements were taken to calculate the prostatic volume in cubic millimeters (mm^3).

4. Highest Diameter of the Lesion as a Measure of Tumor Radiologic Progression Using Dynamic MRI [Baseline and Month 12]

   MRI is an imaging technique used to investigate the anatomy and function of the body. Measurements were taken to determine the diameter of the lesions in millimeters (mm).

5. Change From Baseline in Prostate-specific Antigen (PSA) Levels [Baseline and Months 3, 6, 9 and 12]

   Blood was collected and sent to a central laboratory for analysis of PSA reported in milligrams/milliliter (mg/mL). A negative change from baseline indicates improvement. An ANCOVA model fitted with baseline PSA Level and age as covariates was used for analyses.

6. Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score [Baseline and Months 3, 6, 9 and 12]

   The HADS is a 14-item scale that measures anxiety (7-items) and depression (7-items) over the previous week. Each question is answered on a scale of 0 (best) to 3 (worst) for a total possible score of 0 to 42, with higher scores indicating more anxiety and depression. A negative change from baseline indicates improvement. An ANCOVA model fitted with baseline HADS score and age as covariates was used for analyses.

7. Change From Baseline in the International Index of Erectile Function (IIEF-5) Questionnaire Score [Baseline and Months 3, 6, 9 and 12]

   The IIEF-5, a 5 question patient completed questionnaire, is a measure of erectile dysfunction over the past 6 months. Each question is answered on a scale of 1 (worst) to 5 (best). Total score ranges from 5 to 25 with higher scores indicating better function (5-7: severe; 8-11: moderate; 12-16: mild to moderate;17-21: mild; 22-25: none). A positive change from baseline indicates improvement. A negative change from baseline indicates a worsening. An ANCOVA model fitted with baseline IIEF-5 score and age as covariates was used for analyses.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 80 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Is an out-patient 50 to 80 years old.

2. Has read, understood, signed and dated the informed consent.

3. Has indolent prostate cancer defined by:

• Clinical Stage T1c or T2a.

• Biopsy cores of which at least 12 reveal the presence of positive cores and the absence of cores with tumor length > 3 mm.

• Absence of Grade 4 cells (Gleason <7).

• Prostate specific antigen (PSA) levels <10 ng/ml.

1. Has a life expectancy > 5 years.

2. Has accepted the principle of active surveillance.

3. Is willing to participate in the study for a minimum of fifteen months.

Exclusion Criteria:

1. Has prior androgen deprivation including a 5-alpha reductase inhibitor (finasteride or dutasteride) within the last 6 months.

2. Has psychological failure related to prostate cancer therapy.

3. Has any active disorder likely to affect the conduct of the study or the patient's prognosis during the study.

4. Has a mental deficiency or any other reason that may hinder the understanding or strict application of the protocol.

5. Is under judicial protection, tutorship or curatorship.

6. Is unlikely to attend control visits.

7. Is currently enrolled in an investigational study or has participated in another investigational study within the last 3 months.

8. Has an allergy or hypersensitivity to any components of leuprorelin (Enantone LP) 11.25 mg or Casodex® 50 mg.

9. Has a medical history of severely impaired hepatic function linked to bicalutamide or a pathological cause.

10. Has testosterone level < 0.5 ng/ml.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tenon Hospital Paris France	Paris		France	75020
2	Ouzid, Paris La Défense,	Paris		France	92977

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02085252
• Other Study ID Numbers: FR-LEU-002; 2012-002653-35; U1111-1146-5402
• First Posted: Mar 12, 2014
• Last Update Posted: Jun 28, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Prostatic Neoplasms; Bicalutamide; Leuprolide

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 22 investigative sites in France from 03 June 2013 to 08 November 2016.
Pre-assignment Detail	Participants with a diagnosis of Prostate Cancer were randomised equally to one of two arms: leuprorelin 11.25 mg or active surveillance. 116 participants were randomized but 1 patient was excluded due to absence of prostate cancer before treatment.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Period Title: Overall Study
STARTED	58	57
COMPLETED	57	53
NOT COMPLETED	1	4

Baseline Characteristics

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance	Total
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.	Total of all reporting groups
Overall Participants	58	57	115
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.22 (5.76)	63.60 (5.56)	64.92 (5.79)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	58 100%	57 100%	115 100%
Region of Enrollment (Count of Participants)
France	58 100%	57 100%	115 100%
Height (centimeters (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters (cm)]	171.85 (6.55)	173.69 (8.08)	172.77 (7.38)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Negative Biopsies at Month 12
Description	Staging biopsy of at least 12 cores were sampled and analyzed according to a centralized biopsy procedure which confirm the results of the first biopsy [presence of positive cores, the absence of core with tumor length > 3 millimeters (mm), and absence Grade 4 cells (Gleason score < 7)]. The Gleason score grades prostate cancer tissue, based on its appearance under a microscope. Scores range from 2 to 10, with a higher score meaning that the cancer tissue is more likely to spread.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised. Participants with missing biopsy results have been excluded from the analysis.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	53	54
Count of Participants [Participants]	28 48.3%	17 29.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Leuprorelin 11.25 mg, Active Surveillance
	Comments	The null hypothesis was that there was no difference between the two treatment strategies.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0318
	Comments	A 2-sided significance level of 5% was used. There was no adjustment for multiple comparisons.
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Number of Participants With Gleason Score ≥ 7
Description	Gleason score grades prostate cancer tissue, based on its appearance under a microscope. Scores range from 2 to 10, with a higher score meaning that the cancer tissue is more likely to spread.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised. Participants with missing Gleason score data are excluded.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	26	34
Count of Participants [Participants]	1 1.7%	3 5.3%

3. Secondary Outcome

Title	Change From Baseline in the International Prostate Symptom Score (I-PSS) Total Symptom (S) Score
Description	The I-PSS is an 8-question tool used to measure prostate symptoms (≤7: mildly symptomatic; 8-19 moderately symptomatic; 20-35 severely symptomatic). The first 7 symptom questions answered on a scale of 0 (never) to 5 (almost always) are used to determine the I-PSS Total S Score for a total possible score of 0 to 35. The 8th question is quality of life and is not reported here. A negative change from baseline indicates improvement. An Analysis of Covariance (ANCOVA) model fitted with baseline I-PSS total score and age as covariates was used for analysis.
Time Frame	Baseline and Months 3, 6, 9 and 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	58	57
Change at Month 3	0.37	1.03
Change at Month 6	-0.38	0.32
Change at Month 9	-1.13	0.64
Change at Month 12	-0.48	0.93

4. Secondary Outcome

Title	Prostatic Volume as a Measure of Tumor Radiologic Progression Using Dynamic Magnetic Resonance Imaging (MRI)
Description	MRI is an imaging technique used to investigate the anatomy and function of the body. Measurements were taken to calculate the prostatic volume in cubic millimeters (mm^3).
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised. Participants with missing MRI data are excluded from analyses. Number analyzed is the number of participants with prostatic volume data at the given time-point.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	56	57
Baseline	48.48 (25.09)	49.44 (25.88)
Month 12	51.47 (28.15)	48.33 (20.18)

5. Secondary Outcome

Title	Highest Diameter of the Lesion as a Measure of Tumor Radiologic Progression Using Dynamic MRI
Description	MRI is an imaging technique used to investigate the anatomy and function of the body. Measurements were taken to determine the diameter of the lesions in millimeters (mm).
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomized and for whom MRI was performed. Participants with missing MRI data are excluded from analyses. Number analyzed is the number of participants with diameter data at the given time-point.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	56	57
Baseline	6.39 (2.80)	7.78 (2.02)
Month 12	6.25 (3.62)	7.69 (2.56)

6. Secondary Outcome

Title	Change From Baseline in Prostate-specific Antigen (PSA) Levels
Description	Blood was collected and sent to a central laboratory for analysis of PSA reported in milligrams/milliliter (mg/mL). A negative change from baseline indicates improvement. An ANCOVA model fitted with baseline PSA Level and age as covariates was used for analyses.
Time Frame	Baseline and Months 3, 6, 9 and 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	58	57
Change at Month 3	-4.61	0.22
Change at Month 6	-3.27	0.85
Change at Month 9	-1.46	0.71
Change at Month 12	0.17	0.76

7. Secondary Outcome

Title	Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score
Description	The HADS is a 14-item scale that measures anxiety (7-items) and depression (7-items) over the previous week. Each question is answered on a scale of 0 (best) to 3 (worst) for a total possible score of 0 to 42, with higher scores indicating more anxiety and depression. A negative change from baseline indicates improvement. An ANCOVA model fitted with baseline HADS score and age as covariates was used for analyses.
Time Frame	Baseline and Months 3, 6, 9 and 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	58	57
Change at Month 3	-0.83	-1.20
Change at Month 6	-1.44	-1.58
Change at Month 9	-2.06	-1.76
Change at Month 12	-1.87	-1.95

8. Secondary Outcome

Title	Change From Baseline in the International Index of Erectile Function (IIEF-5) Questionnaire Score
Description	The IIEF-5, a 5 question patient completed questionnaire, is a measure of erectile dysfunction over the past 6 months. Each question is answered on a scale of 1 (worst) to 5 (best). Total score ranges from 5 to 25 with higher scores indicating better function (5-7: severe; 8-11: moderate; 12-16: mild to moderate;17-21: mild; 22-25: none). A positive change from baseline indicates improvement. A negative change from baseline indicates a worsening. An ANCOVA model fitted with baseline IIEF-5 score and age as covariates was used for analyses.
Time Frame	Baseline and Months 3, 6, 9 and 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants with prostate cancer who signed informed consent and were randomised.

Arm/Group Title	Leuprorelin 11.25 mg	Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.	Active surveillance is close medical monitoring of prostate cancer for any changes.
Measure Participants	58	57
Change at Month 3	-7.40	0.00
Change at Month 6	-5.87	0.01
Change at Month 9	-1.94	-0.38
Change at Month 12	-1.68	-0.02

Adverse Events

Time Frame	First dose of study drug to the End of Study Visit (Up to 12 Months)
Adverse Event Reporting Description	At each visit the investigator documented any occurrence of adverse events and abnormal laboratory findings. Any event reported by the participant or observed by the investigator was recorded.
Arm/Group Title	Leuprorelin 11.25 mg		Active Surveillance
Arm/Group Description	Active surveillance after a single subcutaneous injection of leuprorelin 11.25 mg and bicalutamide 50 mg, tablet, orally, once daily, to prevent flare-up for 15 days.		Active surveillance is close medical monitoring of prostate cancer for any changes.
All Cause Mortality
	Leuprorelin 11.25 mg		Active Surveillance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Leuprorelin 11.25 mg		Active Surveillance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/58 (6.9%)		3/57 (5.3%)
Cardiac disorders
Atrial flutter	1/58 (1.7%)		0/57 (0%)
Ear and labyrinth disorders
Deafness	1/58 (1.7%)		0/57 (0%)
Gastrointestinal disorders
Pancreatic neoplasm	0/58 (0%)		1/57 (1.8%)
Infections and infestations
Erysipelas	0/58 (0%)		1/57 (1.8%)
Renal and urinary disorders
Urinary tract disorder	0/58 (0%)		1/57 (1.8%)
Vascular disorders
Fatigue	1/58 (1.7%)		0/57 (0%)
Dizziness	1/58 (1.7%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	Leuprorelin 11.25 mg		Active Surveillance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/58 (69%)		11/57 (19.3%)
General disorders
Fatigue	4/58 (6.9%)		0/57 (0%)
Infections and infestations
Bronchitis	3/58 (5.2%)		2/57 (3.5%)
Musculoskeletal and connective tissue disorders
Back pain	2/58 (3.4%)		4/57 (7%)
Nervous system disorders
Headache	3/58 (5.2%)		0/57 (0%)
Psychiatric disorders
Erectile dysfunction	7/58 (12.1%)		2/57 (3.5%)
Renal and urinary disorders
Dysuria	4/58 (6.9%)		2/57 (3.5%)
Reproductive system and breast disorders
Erectile dysfunction	3/58 (5.2%)		0/57 (0%)
Hot flush	17/58 (29.3%)		0/57 (0%)
Libido decreased	6/58 (10.3%)		0/57 (0%)
Vascular disorders
Hot flush	6/58 (10.3%)		0/57 (0%)
Flushing	9/58 (15.5%)		0/57 (0%)
Hypertension	1/58 (1.7%)		3/57 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.