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Impact of Atorvastatin on Prostate Cancer Progression During ADT (ESTO2)

Primary Purpose

Metastatic Prostate Cancer, Recurrent Prostate Cancer

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Atorvastatin 80mg
Placebo oral capsule
Sponsored by
Tampere University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Prostate Cancer focused on measuring Prostate cancer, Castration resistance, Cholesterol lowering drug, Cholesterol, Atorvastatin, Survival, Mortality

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Histopathologically confirmed metastatic (radiologically confirmed bone or soft tissue metastasis or enlarged lymph nodes at minimum 15 mm in diameter beyond the pelvic lymph nodes) or recurrent (requiring treatment after curative-intent surgery or radiotherapy) adenocarcinoma of the prostate for which androgen deprivation or antiandrogen therapy (GnRH agonist/antagonist, bicalutamide/flutamide, surgical castration or enzalutamide/abiraterone monotherapy) is initiated as definitive treatment no longer than 3 months before recruitment

    • previous prostatectomy and radiation therapy allowed
    • ADT/antiandrogen therapy for neoadjuvant hormone therapy is not included
  • Willingness to participate and signing of informed consent

Exclusion Criteria:

  • Statin use at the time of recruitment or within 6 months of it
  • Previous adverse effects during statin therapy
  • Familial hypercholesterolemia or very high total cholesterol (9.3 mmol/l or above)
  • Clinically significant renal insufficiency (serum creatinine above 170 µmol/l) or liver insufficiency (serum alanine aminotransferase more than 2x above the upper limit of normal range)
  • Use of drugs that may interact with statins (St John's Wort, HIV protease inhibitors, ciclosporin, macrolide antibiotics, fucidic acid, phenytoin, carbamazepine, dronedarone or oral antifungal medication).

Sites / Locations

  • Herlev and Gentofte Hospital
  • Tartu University HospitalRecruiting
  • Helsinki University Hospital, Department of UrologyRecruiting
  • Central Finland central hospitalRecruiting
  • Kuopio University Hospital, Department of Urology
  • Seinäjoki Central Hospital, Department of SurgeryRecruiting
  • Tampere University HospitalRecruiting
  • Turku University HospitalRecruiting
  • The Hospital of TelemarkRecruiting
  • The Hospital of VestfoldRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Atorvastatin

Placebo

Arm Description

Capsules of atorvastatin. Daily dose of 80 mg for max. 10 years or until development of castration resistance.

Identical capsules as in the atorvastatin arm, but including no active ingredient. Used daily for max. 10 years or until development of castration resistance

Outcomes

Primary Outcome Measures

Castration resistance
Castration resistance is defined as PSA progression (three consecutive PSA rises measured at least 1 week apart with two > 50% increases over the nadir and PSA > 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (< 1.73 nmol/l; 50 ng/dl) during ADT.

Secondary Outcome Measures

Lipid levels
Change in serum lipid levels during the intervention. Measured at baseline and in every follow-up visit. Results are blinded from the investigators and participants before the final analysis
Prostate cancer mortality
Followed through Finnish national registries after reaching the primary end-point
Overall survival
Followed through Finnish national registries after reaching the primary end-point
Circulating cell-free DNA
Occurrence of adverse tumor traits predicting development of castration resistance in circulating cell free DNA
Fasting blood glucose
To see how ADT affects glucose tolerance and whether atorvastatin intervention has any effect on it
Occurrence of cardiovascular events during ADT
Any cardiovascular events as described by the participant or evident from the patient files during the course of follow-up. Followed via national registries after meeting the primary end-point.
General quality of life (QOL)
Score from validated QOL questionnaire EORTC QLQ-C30 (range 0-100, with 100 denoting highest quality of life)
Prostate cancer-specific quality of life (QOL)
Score from validated QOL questionnaire EORTC QLQ-PR25 (range 0-100, with 100 denoting highest quality of life)

Full Information

First Posted
June 25, 2018
Last Updated
October 19, 2022
Sponsor
Tampere University Hospital
Collaborators
Turku University Hospital, Central Finland Hospital District, Tartu University Hospital, University of Aarhus, Fimlab laboratories, Helsinki University Central Hospital, Kuopio University Hospital, Oulu University Hospital, Seinajoki Central Hospital, The Hospital of Vestfold, Telemark Hospital Trust
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1. Study Identification

Unique Protocol Identification Number
NCT04026230
Brief Title
Impact of Atorvastatin on Prostate Cancer Progression During ADT
Acronym
ESTO2
Official Title
Impact of Atorvastatin on Prostate Cancer Progression After Initiation of Androgen Deprivation Therapy - Lipid Metabolism as a Novel Biomarker to Predict Prostate Cancer Progression
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 15, 2019 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tampere University Hospital
Collaborators
Turku University Hospital, Central Finland Hospital District, Tartu University Hospital, University of Aarhus, Fimlab laboratories, Helsinki University Central Hospital, Kuopio University Hospital, Oulu University Hospital, Seinajoki Central Hospital, The Hospital of Vestfold, Telemark Hospital Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This randomized double-blind placebo-controlled trial tests whether intervention with atorvastatin delays development of castration resistance compared to placebo during androgen deprivation therapy (ADT) for prostate cancer.
Detailed Description
Cholesterol-lowering statin drugs have been reported to lower proliferation activity in prostate cancer, delay occurrence of castration resistance and reduce the risk of prostate cancer death. Therefore, it is important to test statins' efficacy in addition to conventional prostate cancer treatment in a randomized, placebo-controlled trial. This phase 3 randomized double-blind placebo-controlled trial will explore whether intervention with atorvastatin delays prostate cancer progression i.e. development of castration resistance compared to placebo during androgen deprivation therapy (ADT) for metastatic or recurrent prostate cancer. Secondary objectives include exploring whether atorvastatin lowers prostate cancer-specific or overall mortality compared to placebo, and to demonstrate whether changes in serum lipid parameters predict disease recurrence and occurrence of adverse genomic changes predicting castration resistance among prostate cancer patients during ADT. The study recruitment target is 400 participants who start ADT as management of metastatic or recurrent prostate cancer. These men will be randomized 1:1 (200 + 200) to receive blinded study drug, either 80 mg of atorvastatin daily or placebo until disease recurrence i.e. development of castration resistance or for a maximum of five years. The study will be carried out in collaboration between urological departments of University Hospitals in Finland as a project of the national FinnProstata study group, Herlev University Hospital in Denmark, Vestfold and Telemark hospitals in Norway and the Tartu University Hospital in Estonia. Follow-up is continued until the primary end-point, development of castration resistance. After this the participants will be given the opportunity to voluntarily carry on with the blinded intervention for maximum time of ten year to observe effects on survival after development of castration resistance. Blinding will be lifted after the follow-up is complete for all study participants. Castration resistance is defined as prostate-specific antigen (PSA) progression (three consecutive rises of PSA measured at least 1 week apart with two > 50% increases over the nadir and PSA > 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (< 1.73 nmol/l; 50 ng/dl) during ADT.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Prostate Cancer, Recurrent Prostate Cancer
Keywords
Prostate cancer, Castration resistance, Cholesterol lowering drug, Cholesterol, Atorvastatin, Survival, Mortality

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Atorvastatin
Arm Type
Experimental
Arm Description
Capsules of atorvastatin. Daily dose of 80 mg for max. 10 years or until development of castration resistance.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Identical capsules as in the atorvastatin arm, but including no active ingredient. Used daily for max. 10 years or until development of castration resistance
Intervention Type
Drug
Intervention Name(s)
Atorvastatin 80mg
Other Intervention Name(s)
Lipitor
Intervention Description
Capsules including 80 mg of atorvastatin
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
Similar capsules as in the atorvastatin arm, but without the active ingredient
Primary Outcome Measure Information:
Title
Castration resistance
Description
Castration resistance is defined as PSA progression (three consecutive PSA rises measured at least 1 week apart with two > 50% increases over the nadir and PSA > 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (< 1.73 nmol/l; 50 ng/dl) during ADT.
Time Frame
From date of randomization until the date of first occurrence of castration resistance, assessed up to 60 months
Secondary Outcome Measure Information:
Title
Lipid levels
Description
Change in serum lipid levels during the intervention. Measured at baseline and in every follow-up visit. Results are blinded from the investigators and participants before the final analysis
Time Frame
From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 6 month intervals up to 60 months
Title
Prostate cancer mortality
Description
Followed through Finnish national registries after reaching the primary end-point
Time Frame
From date of randomization until the date of prostate cancer death, assessed up to 60 months
Title
Overall survival
Description
Followed through Finnish national registries after reaching the primary end-point
Time Frame
From date of randomization until the date of death due to any cause, assessed up to 60 months
Title
Circulating cell-free DNA
Description
Occurrence of adverse tumor traits predicting development of castration resistance in circulating cell free DNA
Time Frame
At enrollment and at occurrence of castration resistance, assessed up to 60 months
Title
Fasting blood glucose
Description
To see how ADT affects glucose tolerance and whether atorvastatin intervention has any effect on it
Time Frame
From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 6 month intervals up to 60 months
Title
Occurrence of cardiovascular events during ADT
Description
Any cardiovascular events as described by the participant or evident from the patient files during the course of follow-up. Followed via national registries after meeting the primary end-point.
Time Frame
From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 6 month intervals up to 60 months
Title
General quality of life (QOL)
Description
Score from validated QOL questionnaire EORTC QLQ-C30 (range 0-100, with 100 denoting highest quality of life)
Time Frame
From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 12 month intervals up to 60 months
Title
Prostate cancer-specific quality of life (QOL)
Description
Score from validated QOL questionnaire EORTC QLQ-PR25 (range 0-100, with 100 denoting highest quality of life)
Time Frame
From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 12 month intervals up to 60 months

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histopathologically confirmed metastatic (radiologically confirmed bone or soft tissue metastasis or enlarged lymph nodes at minimum 15 mm in diameter beyond the pelvic lymph nodes) or recurrent (requiring treatment after curative-intent surgery or radiotherapy) adenocarcinoma of the prostate for which androgen deprivation or antiandrogen therapy (GnRH agonist/antagonist, bicalutamide/flutamide, surgical castration or enzalutamide/abiraterone monotherapy) is initiated as definitive treatment no longer than 3 months before recruitment previous prostatectomy and radiation therapy allowed ADT/antiandrogen therapy for neoadjuvant hormone therapy is not included Willingness to participate and signing of informed consent Exclusion Criteria: Statin use at the time of recruitment or within 6 months of it Previous adverse effects during statin therapy Familial hypercholesterolemia or very high total cholesterol (9.3 mmol/l or above) Clinically significant renal insufficiency (serum creatinine above 170 µmol/l) or liver insufficiency (serum alanine aminotransferase more than 2x above the upper limit of normal range) Use of drugs that may interact with statins (St John's Wort, HIV protease inhibitors, ciclosporin, macrolide antibiotics, fucidic acid, phenytoin, carbamazepine, dronedarone or oral antifungal medication).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Teemu Murtola, MD, PhD
Phone
+358-3 311 65015
Email
teemu.murtola@uta.fi
First Name & Middle Initial & Last Name or Official Title & Degree
Aino Siltari, PhD
Email
aino.siltari@helsinki.fi
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Teemu Murtola, MD, PhD
Organizational Affiliation
Tampere University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Otto Ettala, MD, PhD
Organizational Affiliation
Turku University Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Heikki Seikkula
Organizational Affiliation
Central Finland Central Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Herlev and Gentofte Hospital
City
Herlev
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mikkel Fode, MD, PhD
Email
mikkelfode@gmail.com
First Name & Middle Initial & Last Name & Degree
Peter Oestergren, MD, PhD
Email
peter.busch.oestergren@regionh.dk
Facility Name
Tartu University Hospital
City
Tartu
Country
Estonia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andres Kotsar, MD, PhD
Email
andres.kotsar@gmail.com
Facility Name
Helsinki University Hospital, Department of Urology
City
Helsinki
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antti Rannikko, MD,PhD
Email
antti.rannikko@hus.fi
Facility Name
Central Finland central hospital
City
Jyväskylä
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Heikki Seikkula, MD, PhD
Email
heikki.seikkula@ksshp.fi
Facility Name
Kuopio University Hospital, Department of Urology
City
Kuopio
Country
Finland
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arto Salonen, MD,PhD
Email
arto.salonen@kuh.fi
Facility Name
Seinäjoki Central Hospital, Department of Surgery
City
Seinäjoki
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Timo Marttila, MD,PhD
Email
timo.marttila@epshp.fi
Facility Name
Tampere University Hospital
City
Tampere
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Teemu Murtola, MD, PhD
Email
teemu.murtola@tuni.fi
Facility Name
Turku University Hospital
City
Turku
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Otto Ettala, MD, PhD
Email
otto.ettala@utu.fi
Facility Name
The Hospital of Telemark
City
Skien
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rasmus Nilsson, MD, PhD
Email
Rasmus.Nilsson@sthf.no
Facility Name
The Hospital of Vestfold
City
Tønsberg
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sven Lofferen, MD, PhD
Email
sven.loffeler@siv.no

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Sharing of individual-level data is not allowed by ethics board
Citations:
PubMed Identifier
35487730
Citation
Siltari A, Riikonen J, Koskimaki J, Pakarainen T, Ettala O, Bostrom P, Seikkula H, Kotsar A, Tammela T, Helminen M, Raittinen PV, Lehtimaki T, Fode M, Ostergren P, Borre M, Rannikko A, Marttila T, Salonen A, Ronkainen H, Loffeler S, Murtola TJ. Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol. BMJ Open. 2022 Apr 29;12(4):e050264. doi: 10.1136/bmjopen-2021-050264.
Results Reference
derived

Learn more about this trial

Impact of Atorvastatin on Prostate Cancer Progression During ADT

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