LIpitor and biGuanide to Androgen Delay Trial

Study Overview
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Brief Summary
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This study is a randomized trial examining the administration of a combination of biguanide metformin and atorvastatin (Lipitor) to men who are experiencing rising prostate-specific antigen (PSA) levels, despite having undergone radical therapy (surgery and/or radiation).

Official Title
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A Randomized, Double Blind, Trial of Metformin and Atorvastatin in Delaying Androgen Deprivation Therapy Among Men With Rising PSA Following Radical Prostatectomy or Radiotherapy: The LIGAND (LIpitor and biGuanide to Androgen Delay) Trial

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Metformin
* Drug: Atorvastatin
* Drug: Placebo (corresponding to metformin)
* Drug: Placebo (corresponding to atorvastatin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent Histologically confirmed adenocarcinoma of the prostate History of radical therapy (i.e., radical prostatectomy, radiotherapy, brachytherapy or prostatectomy with salvage radiotherapy) Serum testosterone levels 8.0 nmol/L (230 ng/dL) or greater Not currently undergoing treatment for hyperlipidemia or diabetes mellitus LDL-cholesterol levels 5 mmol/L or lower HgA1c 6.5% or lower PSA levels between 2 and 5 ng/mL Exclusion Criteria: Subjects that have been treated for prostate cancer with any of the following: i. Cytotoxic chemotherapy; ii. Hormonal therapy within past 3 years; iii. Oral glucocorticoids; iv. Gonadotropin-releasing hormone (GnRH) analogues (e.g., leuprolide, goserelin, degarelix) Past treatment with the 5-α reductase inhibitors finasteride and dutasteride within past 5 years Past treatment with drugs with antiandrogenic properties (e.g., flutamide, bicalutamide, ketoconazole, progestational agents) within 6 months prior to screening Use of metformin or statins within past 2 years Planned or concurrent use of metformin, sulfonylureas, thiazolidinediones or insulin for any reason Known hypersensitivity or intolerance to metformin or atorvastatin Any clinically significant laboratory abnormalities (e.g., severe renal or hepatic impairment) which in the judgment of the investigator would affect the patient's health or the outcome of the trial Any condition associated with increased risk of metformin-associated lactic acidosis (e.g., congestive heart failure defined as New York Heart Association (NYHA) class III or IV, history of any type of acidosis, habitual intake of 4 or more alcoholic beverages per day) Abnormal liver function test Abnormal organ and marrow function

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin and Atorvastatin<br>Atorvastatin 20 mg once daily until progression with one month run-in of 850 mg metformin once daily, followed by 850 mg twice daily of metformin until progression. | Drug: Metformin<br>* One month run-in of 850 mg metformin once daily, followed by 850 mg twice daily of metformin until progression.<br>* Other names: biguanide;Drug: Atorvastatin<br>* Atorvastatin 20 mg once daily until progression.<br>* Other names: lipitor;|
| Placebo Comparator: Placebo<br>One placebo tablet (corresponding to atorvastatin) once daily until progression, with one month of one placebo tablet (corresponding to metformin) once daily, followed by one placebo tablet twice daily until progression. | Drug: Placebo (corresponding to metformin)<br>* One month of one placebo tablet (corresponding to metformin) once daily, followed by one placebo tablet twice daily until progression.<br>Drug: Placebo (corresponding to atorvastatin)<br>* One placebo tablet (corresponding to atorvastatin) once daily until progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to disease progression (defined as PSA rise to 10 ng/mL or greater, development of clinically overt metastases) or patient/physician desire for androgen deprivation therapy. |  | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to androgen deprivation therapy |  | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Time to PSA progression |  | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Time to disease progression |  | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Body mass index | Relationship between body mass index and response to anti-metabolic and anti-cholesterol therapy | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Circulating glycated hemoglobin levels | Relationship between circulating glycated hemoglobin levels and response to anti-metabolic and anti-cholesterol therapy | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| C-peptide levels | Relationship between C-peptide levels and response to anti-metabolic and anti-cholesterol therapy | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Adipokine levels | Relationship between adipokine levels and response to anti-metabolic and anti-cholesterol therapy | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| LDL/HDL cholesterol levels | Relationship between LDL/HDL cholesterol levels and response to anti-metabolic and anti-cholesterol therapy | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Triglyceride levels | Relationship between triglyceride levels and response to anti-metabolic and anti-cholesterol therapy | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 
| Incidence of adverse events during administration of metformin and atorvastatin to men with prostate cancer. | Assessment of incidence of adverse events from the administration of metformin and atorvastatin to men with prostate cancer. | From date of randomization until the date of progression or patient/physician desire for androgen deprivation therapy, whichever comes first, assessed up to 36 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, atorvastatin, prostate-specific antigen, biochemical recurrence