Prostatic Hyperplasia
Conditions
Keywords
prostate cancer, PIN, polyphenon E, EGCG
Brief summary
The purpose of this study was to determine whether the daily consumption of decaffeinated green tea catechins (Polyphenon E®) for 1 year reduces the rate of progression to prostate cancer (PCa) in men diagnosed with HGPIN or ASAP. The aim was to recruit and treat 240 (120 men/arm) men diagnosed with the prostate condition HGPIN or ASAP with a capsule form of standardized green tea extract called Polyphenon E or placebo for a 12-month period and see if it can prevent progression of the prostate condition to prostate cancer. Investigators wanted to see if Polyphenon E reduces lower urinary tract symptoms and if this can be taken safely over one year. Investigators wanted to study how Polyphenon E is able to slow the progression to prostate cancer, or the mechanism of action of Polyphenon E. If the safety and the effects of Polyphenon E on slowing down the progression of prostate cancer is shown in our study, this will be a safe way of treating men who are at high risk or men like you who have a prostate condition that increases your chances of getting prostate cancer, so that we can prevent prostate cancer in the future.
Detailed description
At the baseline/randomization visit, a QOL (Medical Outcomes Study Short Form-36) and lower urinary tract symptoms (LUTS) score assessment will be completed; urine and serum will be collected for measurement of diagnostic markers; plasma will be collected for measurement of baseline catechin levels; serum will be collected for banking; and diet recall forms will be collected. Participants will be equally randomized to blinded treatment with either Polyphenon E 200 mg EGCG bid or matching placebo, and an initial supply of study drug will be dispensed. All participants will also be provided with a standard multivitamin/mineral supplement to assure consistent, appropriate nutrient intake among study participants. The planned intervention period is 12 months; participants will return for monthly clinic visits during the intervention period. At each monthly clinic visit, blood will be drawn for repeat hepatic function panel, lactate dehydrogenase (LDH) and prothrombin time/partial thromboplastin time (PT/PTT), and participants will be interviewed to review and capture information from study agent intake log (pill count), assess signs and symptoms and concomitant medications; additional study medication will be dispensed as needed. After 3 and 6 months of intervention, blood will be drawn for serum chemistry and hematology, and LUTS and QOL assessments will be performed. In addition, at the 6 month visit, two-day diet recall forms will be collected, blood will be drawn for plasma catechin measurements and serum banking, serum and urine will be collected for diagnostic marker measurement, and repeat digital rectal exam (DRE) and prostate specific antigen (PSA) will be performed. If there is a palpable prostate nodule or confirmed PSA increase (\>0.75 ng/ml) at 6 months, a repeat biopsy will be performed. If the 6-month biopsy shows evidence of disease progression, participants will stop intervention and proceed to the post-intervention assessment; otherwise, intervention will continue through month 12. At the end of intervention (maximum of 12 months), a repeat prostate biopsy will be performed for post-intervention endpoint measurements. In addition, the physical exam and DRE, LUTS and QOL will be repeated, and 2-day diet recall forms will be collected. Blood will be drawn for serum chemistry and hematology, PSA, hepatic function panel, LDH, PT/PTT; serum and urine will be collected for diagnostic marker measurement; plasma will be collected for catechin measurements; and serum will be collected for banking. Participants will be interviewed to review and capture information from study agent intake log (pill count), assess signs and symptoms and concomitant medications.
Interventions
DRUGPolyphenon E
Polyphenon E, at a dose of 400 mgs EGCG (200 mgs BID) for 1 year in men diagnosed with HGPIN and ASAP.
DRUGPlacebo
Matching placebo BID
Sponsors
National Cancer Institute (NCI)
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Men with a diagnosis of HGPIN or ASAP in a minimum of 1 of 8 cores from a biopsy performed within six months of study entry. Diagnosis of HGPIN or ASAP (which includes men with ASAP and HGPIN) via trans-rectal ultrasound (TRUS biopsy) is also considered acceptable for inclusion. * Prostate biopsy with a minimum of 8 cores performed within 6 months of study entry that shows no evidence of cancer. * 30-80 years of age at the time of registration * PSA ≤10 ng/ml * Omnivorous diet * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Participants must have normal organ and marrow function as demonstrated by the following parameters being within normal institutional limits: complete blood count (CBC); liver function tests (LFTs); albumin, total and direct bilirubin, alkaline phosphatase, aspartic transaminase (AST), alanine transaminase (ALT), and total protein), PT/PTT, and LDH; serum creatinine \<1.5 mg/dl or measured creatinine clearance 60 cc/min * Absence of consumption of toremifene citrate, finasteride, testosterone, dehydroepiandrosterone (DHEA) or other testosterone-like supplements or medications which have known impact on PSA within 30 days of informed consent, or dutasteride within 90 days of informed consent * Absence of consumption of any nutritional or herbal supplements containing green tea or green tea polyphenols * No or low regular tea consumption (no more than 3 servings of hot tea or 6 servings of iced tea per week) * Willing to discontinue current vitamin/mineral supplement use and substitute with a standard multivitamin supplement provided for the study * Willing to use an effective method of contraception, if the partner is of child-bearing age, while on study * Willing to comply with proposed visit and treatment schedule * Able to understand and willing to sign a written informed consent document
Exclusion criteria
* Evidence of acute prostatitis or urinary tract infection at the time of PSA measurement; men may be enrolled 30 days after completion of treatment, provided all other eligibility criteria are met * Current or prior history of prostate cancer or other malignancies (exceptions include non-melanoma skin cancer or other cancer with no evidence of tumor recurrence 5 years after definitive treatment) * History of renal or hepatic disease, including history of hepatitis B, C or delta * Participation in any other investigational study or use of any other investigational agents within 30 days of study entry * History of allergic reactions attributed to tea or other compounds of similar chemical or biologic composition to Polyphenon E or the inactive components present in Polyphenon E and placebo capsules. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any psychological, familial, sociological or other concomitant condition that would not allow adequate compliance with the study protocol * History of medical conditions that may predispose the participant to gastrointestinal bleeding (acute or chronic gastritis or colitis, or acute diverticulitis or hemorrhoids) * Members of all races and ethnic groups are eligible for this trial. Since this is an investigation targeting men with HGPIN or ASAP, women are not eligible for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Progression From HGPIN to ASAP or PCa | 12 months | Analyses of participants reaching a definitive endpoint. Number of baseline HGPIN participants who progressed to ASAP or PCa. |
| Rate of Progression to Prostate Cancer (PCa) | 12 months | Number of participants with diagnosis of high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) who progressed to prostate cancer (PCa) at one year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Serum Total Prostatic Specific Antigen (tPSA) | 12 months | Median ng/mL serum tPSA post treatment, per treatment arm. |
| Occurrence of Grade 3 or Higher Adverse Events (AEs) | 12 months | Number of participants with AEs grade 3 or higher, per treatment arm. |
| Treatment Emergent Adverse Events (AEs) | 12 months | Safety of Polyphenon E (200 mg EGCG bid for one year) in men with HGPIN or ASAP. Number of participants with AEs Possibly or Probably related to treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Scores - Lower Urinary Tract Symptom (LUTS) | 1 year | Change in score from baseline to 1 year. LUTS represent a common conglomeration of storage, voiding, and post-micturition symptoms with reported debilitating effect on quality of life. Symptom severity related to urinary frequency, nocturia, weak urinary stream, hesitancy, intermittency, incomplete bladder emptying and urinary urgency are assessed. We utilized the American Urological Association Symptom Score for the evaluation LUTS in this patient population. Symptom Frequency Scores: 0 = Not at all, 1 = Less than 1 time in 5, 2 = Less than half the time, 3 = About half the time, 4 = More than half the time, 5 = Almost always. Total Symptom Score = Sum of individual scores of the 7 symptoms. (minimum possible score=0; maximum possible score =35; Range of scores and significance: 0-7 mild symptoms; 8-19 moderate symptoms; 20-35 severe symptoms. |
| Effect of Polyphenon E on the Fundamental Molecular Pathways | 12 months | Explore the effects of Polyphenon E on the fundamental molecular pathways contributing to chemopreventive activity of Polyphenon E in the prostate. This exploratory aim is ongoing. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at the Moffitt Cancer Center and 7 other sites in the United States, from September 2008- March 2013.
Pre-assignment details
Participants were block randomized by diagnosis to receive Polyphenon E®) (PolyE) containing 400 mgs (-)-epigallocatechin-3-gallate (EGCG) per day (n=49) or placebo (n=48) for 1 year.
Participants by arm
| Arm | Count |
|---|---|
| Active Comparator: Polyphenon E Treatment Polyphenon E, 200 mg epigallocatechin gallate (EGCG) twice a day (BID) | 49 |
| Placebo Comparator: Placebo Administration Matching placebo twice a day (BID) | 48 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 7 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Active Comparator: Polyphenon E Treatment | Placebo Comparator: Placebo Administration | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 23 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 25 Participants | 52 Participants |
| Age, Continuous | 62 years | 64.10 years | 63.02 years |
| Region of Enrollment United States | 49 Participants | 48 Participants | 97 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 49 Participants | 48 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 47 / 49 | 44 / 48 |
| serious Total, serious adverse events | 4 / 49 | 2 / 48 |
Outcome results
Primary
Rate of Progression From HGPIN to ASAP or PCa
Analyses of participants reaching a definitive endpoint. Number of baseline HGPIN participants who progressed to ASAP or PCa.
Time frame: 12 months
Population: Baseline HGPIN participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Comparator: Polyphenon E Treatment | Rate of Progression From HGPIN to ASAP or PCa | Progressed to ASAP or PCa | 3 participants |
| Active Comparator: Polyphenon E Treatment | Rate of Progression From HGPIN to ASAP or PCa | Progressed to ASAP | 0 participants |
| Placebo Comparator: Placebo Administration | Rate of Progression From HGPIN to ASAP or PCa | Progressed to ASAP or PCa | 10 participants |
| Placebo Comparator: Placebo Administration | Rate of Progression From HGPIN to ASAP or PCa | Progressed to ASAP | 5 participants |
Primary
Rate of Progression to Prostate Cancer (PCa)
Number of participants with diagnosis of high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) who progressed to prostate cancer (PCa) at one year.
Time frame: 12 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Comparator: Polyphenon E Treatment | Rate of Progression to Prostate Cancer (PCa) | 4 participants |
| Placebo Comparator: Placebo Administration | Rate of Progression to Prostate Cancer (PCa) | 6 participants |
Secondary
Median Serum Total Prostatic Specific Antigen (tPSA)
Median ng/mL serum tPSA post treatment, per treatment arm.
Time frame: 12 months
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Comparator: Polyphenon E Treatment | Median Serum Total Prostatic Specific Antigen (tPSA) | 3.5 ng/mL |
| Placebo Comparator: Placebo Administration | Median Serum Total Prostatic Specific Antigen (tPSA) | 4.90 ng/mL |
Secondary
Occurrence of Grade 3 or Higher Adverse Events (AEs)
Number of participants with AEs grade 3 or higher, per treatment arm.
Time frame: 12 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Comparator: Polyphenon E Treatment | Occurrence of Grade 3 or Higher Adverse Events (AEs) | 10 participants |
| Placebo Comparator: Placebo Administration | Occurrence of Grade 3 or Higher Adverse Events (AEs) | 3 participants |
Secondary
Treatment Emergent Adverse Events (AEs)
Safety of Polyphenon E (200 mg EGCG bid for one year) in men with HGPIN or ASAP. Number of participants with AEs Possibly or Probably related to treatment.
Time frame: 12 months
Population: All participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Comparator: Polyphenon E Treatment | Treatment Emergent Adverse Events (AEs) | Probably related to treatment | 5 participants |
| Active Comparator: Polyphenon E Treatment | Treatment Emergent Adverse Events (AEs) | Definitely related to treatment | 0 participants |
| Active Comparator: Polyphenon E Treatment | Treatment Emergent Adverse Events (AEs) | Possibly related to treatment | 7 participants |
| Active Comparator: Polyphenon E Treatment | Treatment Emergent Adverse Events (AEs) | Unlikely to be related to treatment | 7 participants |
| Active Comparator: Polyphenon E Treatment | Treatment Emergent Adverse Events (AEs) | Unrelated to treatment | 193 participants |
| Active Comparator: Polyphenon E Treatment | Treatment Emergent Adverse Events (AEs) | Total | 212 participants |
| Placebo Comparator: Placebo Administration | Treatment Emergent Adverse Events (AEs) | Unrelated to treatment | 156 participants |
| Placebo Comparator: Placebo Administration | Treatment Emergent Adverse Events (AEs) | Unlikely to be related to treatment | 9 participants |
| Placebo Comparator: Placebo Administration | Treatment Emergent Adverse Events (AEs) | Definitely related to treatment | 0 participants |
| Placebo Comparator: Placebo Administration | Treatment Emergent Adverse Events (AEs) | Probably related to treatment | 1 participants |
| Placebo Comparator: Placebo Administration | Treatment Emergent Adverse Events (AEs) | Total | 169 participants |
| Placebo Comparator: Placebo Administration | Treatment Emergent Adverse Events (AEs) | Possibly related to treatment | 3 participants |
Other Pre-specified
Change in Scores - Lower Urinary Tract Symptom (LUTS)
Change in score from baseline to 1 year. LUTS represent a common conglomeration of storage, voiding, and post-micturition symptoms with reported debilitating effect on quality of life. Symptom severity related to urinary frequency, nocturia, weak urinary stream, hesitancy, intermittency, incomplete bladder emptying and urinary urgency are assessed. We utilized the American Urological Association Symptom Score for the evaluation LUTS in this patient population. Symptom Frequency Scores: 0 = Not at all, 1 = Less than 1 time in 5, 2 = Less than half the time, 3 = About half the time, 4 = More than half the time, 5 = Almost always. Total Symptom Score = Sum of individual scores of the 7 symptoms. (minimum possible score=0; maximum possible score =35; Range of scores and significance: 0-7 mild symptoms; 8-19 moderate symptoms; 20-35 severe symptoms.
Time frame: 1 year
Population: Participants with LUTS symptom scores available at baseline and at one year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Straining - change | 0.24 units on a scale | Standard Deviation 0.99 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Incomplete empty - change | 0.07 units on a scale | Standard Deviation 1.77 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Urgency - change | 0.10 units on a scale | Standard Deviation 1.47 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Intermittency - change | 0.21 units on a scale | Standard Deviation 1.32 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Weak stream | 0.24 units on a scale | Standard Deviation 1.12 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Nocturia - change | 0.31 units on a scale | Standard Deviation 1.42 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Total Symptom Score - change | 1.21 units on a scale | Standard Deviation 6.56 |
| Active Comparator: Polyphenon E Treatment | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Frequent urination - change | 0.03 units on a scale | Standard Deviation 1.61 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Total Symptom Score - change | 1.36 units on a scale | Standard Deviation 7.93 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Incomplete empty - change | 0.39 units on a scale | Standard Deviation 1.99 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Frequent urination - change | 0.50 units on a scale | Standard Deviation 1.45 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Nocturia - change | 0.25 units on a scale | Standard Deviation 1.69 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Straining - change | 0.25 units on a scale | Standard Deviation 0.97 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Urgency - change | -0.25 units on a scale | Standard Deviation 1.86 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Weak stream | 0.15 units on a scale | Standard Deviation 1.49 |
| Placebo Comparator: Placebo Administration | Change in Scores - Lower Urinary Tract Symptom (LUTS) | Intermittency - change | -0.04 units on a scale | Standard Deviation 1.4 |
Other Pre-specified
Effect of Polyphenon E on the Fundamental Molecular Pathways
Explore the effects of Polyphenon E on the fundamental molecular pathways contributing to chemopreventive activity of Polyphenon E in the prostate. This exploratory aim is ongoing.
Time frame: 12 months