Study to Assess the Efficacy of Brachytherapy With or Without Hormone Therapy, Using Triptorelin 22.5mg in Patients With Recurrence of Prostate Cancer

Study Overview
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Brief Summary
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The primary objective of the study was to compare the efficacy of brachytherapy versus brachytherapy + triptorelin 22.5 mg (single injection) in subjects with recurrence of prostate cancer previously treated with radiotherapy. Efficacy was to be assessed by biochemical failure-free survival (BFFS) curves from treatment initiation up to 5 years. Secondary objectives included comparing the following: the differences in time to progression of subjects receiving brachytherapy + triptorelin 22.5 mg versus subjects receiving brachytherapy only, the BFFS percentages between both treatment groups at 5 years from treatment initiation, overall survival between both treatment groups, total testosterone changes (from baseline visit up to 12 months) and Prostate Specific Antigen (PSA) levels (from baseline visit up to 60 months of treatment) between both treatment groups, quality of life (QoL) modifications (Spanish version of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire) between the baseline score and the rest of measurements, and to compare safety between both treatment groups.

Detailed Description
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This was a proof-of-concept, prospective, parallel, multicentre, randomised and open-label trial, including a follow-up of all subjects conducted at 11 centres in Spain. Study visits included an inclusion visit (Visit 1), a treatment administration visit (Visit 2), and 9 follow-up visits (Visit 3 to Visit 11) from 3 to 60 months after study treatment administration. All of the procedures performed at these visits were in accordance with routine clinical practice. Subjects were randomised to any one of the two treatment arms (Group 1: brachytherapy only, or Group 2: brachytherapy + triptorelin 22.5 mg). Randomisation was stratified according to the brachytherapy dose rate (low or high dose rate). Visit 1 included the collection of demographic data, a review of clinical details of prostate cancer and its treatment, blood sampling (for Prostate Specific Antigen (PSA), testosterone, and haematology and biochemistry parameters, as appropriate), administration of the QoL questionnaire and International Prostatic Symptom Score (IPSS), and treatment group allocation. Visit 2 included a review of the eligibility criteria, recording of concomitant medications and adverse events (AEs) and study drug administration. Visits 3 to 11 included recording of AEs and concomitant medications, blood sampling and administration of the QoL questionnaire and IPSS. Following the selection visit (Visit 1), all subjects were scheduled to brachytherapy. Those subjects who were randomised to the concomitant hormone therapy group received a single dose of triptorelin 22.5 mg by intramuscular injection at Visit 2, 2 weeks following the selection visit (Visit 1), and preferably 2 months before receiving brachytherapy. One week before and two weeks after triptorelin administration, subjects were permitted to receive an anti-androgen to counteract a transient increase in testosterone levels. The study was prematurely stopped due to the slow enrolment of subjects. Of the planned 86 evaluable subjects, 35 were screened, and 32 were randomised between 3 November 2011 and 26 May 2014. The slow inclusion of subjects was due to several factors, among which there were changes in clinical practice which caused such subjects to be offered alternative treatments to brachytherapy. Due to the small number of subjects, none of the planned efficacy analyses were performed. Instead, the data were analysed as follows: Efficacy data and quality of life (QoL) outcomes were displayed only in listings. Safety information was displayed using listings and summary tables.

Official Title
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Proof-of-concept Multicentre, Prospective, Randomised, Open-label- Parallel-group Clinical Trial to Assess the Efficacy of Brachytherapy With or Without Hormone Therapy Using Triptorelin 22.5 mg 6-month Formulation in Patients With Recurrence of Prostate Cancer Previously Treated With Radiotherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Triptorelin 22.5 mg
* Radiation: Brachytherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A history of prostate cancer (T1-T2-T3 N0 M0), confirmed through histopathology and initially treated with radiotherapy. Age ≤ 75 years. Biochemical failure due to Phoenix criteria (nadir + 2) and local recurrence of the initial prostate cancer, confirmed by prostate biopsy, with neither regional involvement nor distant metastases. Late local recurrence of the initial prostate cancer. A recurrence is late when it appears after longer than 18 months post-radiotherapy. PSA < 10 ng/mL at the time of recurrence. The subject was required to be amenable to brachytherapy treatment. Adequate urinary function according to the questionnaire (IPSS ≤ 20 points). Suitable bone marrow function, determined by: Haemoglobin > 10 g/dL. Neutrophil count > 1.5 x 10^9/L. Platelet count > 100 x 10^9/L. Suitable liver function determined by: serum bilirubin < 1.5 x Upper Normal Level (UNL), and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5xUNL. Suitable renal function determined by: serum creatinine < 1.5 x UNL, or creatinine clearance ≥ 60 mL/min. The subject was required to be ≥ 18 years old. The subject had to give his written informed consent (personally signed and dated) before starting with any study-related procedure. Life expectancy > 5 years. Exclusion Criteria: Evidence of metastatic disease. Previous evidence of hormone-resistant cancer. Lack of availability for performing regular follow-up. Subjects who were receiving or had received either luteinizing hormone-releasing hormone (LH-RH) agonists, or antagonists, over the previous 12 months. Subjects who had been on treatment with other hormone therapies, including antagonists, megestrol acetate, finasteride, dutasteride, any herbaceous product known to reduce the PSA levels, or any systemic corticosteroid, over the previous 4 weeks. Subjects who had previously undergone a radiotherapy treatment that was completed within 18 months of inclusion. Subjects with pre-existing heart failure (New York Heart Association class III or IV), or with a myocardial infarction within 6 months of inclusion. Subjects with a significant co-existing disease or an active infection. Subjects who had been treated with investigational therapies within 4 weeks prior to the brachytherapy ± triptorelin treatment. Subjects with known hypersensitivity to triptorelin, LH-RH, other LH-RH-analogous agonists, or any excipients in triptorelin 22.5 mg. Subjects with a mental condition that prevented them from understanding the nature, the scope and the potential consequences of this study, and/or subjects who showed an uncooperative attitude.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brachytherapy + Triptorelin 22.5 mg<br>Brachytherapy: Low or high dose rate. Triptorelin: A single, intramuscular injection (22.5 mg), preferably 2 months before brachytherapy. | Drug: Triptorelin 22.5 mg<br>* Triptorelin: A single, intramuscular injection (22.5 mg), preferably 2 months before brachytherapy.<br>Radiation: Brachytherapy<br>* Brachytherapy: Low or high dose rate.<br>|
| Active Comparator: Brachytherapy<br>Brachytherapy: Low or high dose rate. | Radiation: Brachytherapy<br>* Brachytherapy: Low or high dose rate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Failure-free Survival (BFFS) | BFFS was determined by a prostate-specific antigen (PSA) increase of 2 nanograms per millilitre (ng/mL) or more in comparison with the pre-study nadir PSA and confirmed in the course of follow-up by a second value 3 weeks later or longer over the 5 year follow-up. Time to BFFS was defined from treatment initiation to the first time when PSA increase of 2 ng/mL was observed. As the study was prematurely terminated, no analyses were conducted. Data for BFFS are listed by subject for those individuals who reported biochemical failure. Time (in months) to biochemical failure is relative to the date of brachytherapy. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression (in months) was measured from the informed consent date to the date of first event occurrence. Progression was defined as either: death from all causes or disease progression (defined as PSA increased by 2 ng/mL as compared to the pre-trial nadir PSA, confirmed during follow-up by a second value after 3 or more weeks, or the diagnosis of a new clinical recurrence of their prostate cancer (metastasis, new injury, etc.)). As the study was prematurely terminated, no analyses were conducted. Data for time to progression are listed by subject for those individuals who reported progression. | Up to 5 years | 
| BFFS Percentage 5 Years From Treatment Initiation | A subject had a biochemical failure if there was an increase of PSA of 2 ng/mL or more in comparison with the pre-study nadir PSA confirmed in the course of follow-up by a second value after 3 or more weeks or with diagnosis of a new clinical recurrence of their prostate cancer over the 5 year follow-up. | 5 years | 
| Overall Survival | Overall survival was defined as the time in months from diagnosis (biopsy date for local recurrence) to death due to any cause, the last visit or the loss to follow-up. | 5 years | 
| Number of Participants With Change in Total Serum Testosterone Levels From Baseline at 3, 6 and 12 Months | Blood samples were drawn for serum testosterone at baseline (Visit 1) and then at 3, 6 and 12 months. Changes from baseline in total serum testosterone levels in relation to the normal parameter ranges are indicated. WNR = Within Normal Range, BNR= Below Normal Range and ANR = Above Normal Range. | Baseline and 3, 6 and 12 months | 
| Number of Participants With Change in Total Serum PSA Levels From Baseline at 3, 6 and 12 Months | Blood samples were drawn for serum PSA at baseline (Visit 1) and at 3, 6 and 12 months. Changes from baseline in total serum PSA levels in relation to the normal parameter ranges are indicated. WNR = Within Normal Range, BNR= Below Normal Range and ANR = Above Normal Range. | Baseline and 3, 6 and 12 months | 
| Change in Quality of Life (QoL) Modifications (Spanish Version of the Expanded Prostate Cancer Index Composite (EPIC) Questionnaire) From Baseline at 5 Years | EPIC assessed the disease-specific aspects of prostate cancer and its therapies and comprised four summary domains (Urinary, Bowel, Sexual and Hormonal). Factor analysis supported dividing the Urinary Domain Summary Score into two different Incontinence and Irritative/Obstructive subscales. In addition, each Domain Summary Score had measurable Function Subscale and Bother Subscale components. Response options for each EPIC item formed a Likert scale, and multi-item scale scores were transformed linearly to a 0-100 scale, with higher scores representing better Health-Related QoL. | Baseline and 5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent Prostate Carcinoma, Brachytherapy, Triptorelin, Hormone Therapy