madman
Super Moderator
Testosterone replacement in prostate cancer survivors with testosterone deficiency: study protocol of a randomized controlled trial (2022)
Rodrigo J. Valderrábano, MD, MS; Karol Pencina, Ph.D.; Thomas W. Storer, Ph.D.; Kieran F. Reid Ph.D., MPH, Adam S. Kibel, MD, Arthur L. Burnett, MD; Grace Huang, MD, MS; Tanya Dorff, MD; Fabiola Privat, BS; Catherine Ghattas-Puylara, MPH; Lauren Wilson, RNP, Nancy K. Latham, Ph.D.; Mats Holmberg, MD Shalender Bhasin MB, BS
ABSTRACT
Background. Most men diagnosed with prostate cancer today have an organ-confined disease and a low risk of disease recurrence after radical prostatectomy. Testosterone deficiency in prostate cancer survivors contributes to impaired health-related quality of life but testosterone treatment is viewed as a contraindication in this population.
Objectives. We describe the design of the first randomized trial to determine the safety and efficacy of testosterone treatment in men who have undergone prostatectomy for nonaggressive prostate cancer and have symptomatic testosterone deficiency.
Methods. Surviving Prostate cancer while Improving the quality of life through Rehabilitation with Testosterone Trial (The SPIRIT Trial) is a randomized, placebo-controlled, double-blind, parallel-group trial in 142 men, >40 years, who have undergone radical prostatectomy for organ-confined prostate cancer, Gleason score <7 (3+4), Stage pT2, N0, M0 lesions and have symptomatic testosterone deficiency and undetectable PSA for >2 years after surgery. Eligible participants are randomized to weekly intramuscular injections of 100-mg testosterone cypionate or placebo for 12 weeks and followed for another 12 weeks. The primary endpoint is a change from baseline in sexual activity. Secondary outcomes include a change in sexual desire, erectile function, energy, lean and fat mass, and physical and cognitive performance. Safety is assessed by monitoring PSA, lower urinary tract symptoms, hemoglobin, and adverse events.
Results. The trial is being conducted at 2 trial sites in Boston, MA, and Baltimore, MD. As of July 30, 2022, 42 participants have been randomized. No PSA or clinical recurrence has been noted to date.
Discussion. Recruitment was slowed by COVID-19-related closures, a slow subsequent ramp-up of research activities, and patient concerns about the safety of testosterone treatment. Despite these challenges, participant retention has been high.
Conclusion. The SPIRIT Trial, a placebo-controlled, randomized trial, will determine whether testosterone replacement therapy is safe and efficacious in correcting symptoms of testosterone deficiency in prostate cancer survivors, and potentially inform clinical practice.
INTRODUCTION
Prostate cancer (PCa) is the most prevalent cancer in men worldwide 1. Most men diagnosed today with prostate cancer have a non-aggressive, organ-confined PCa and radical prostatectomy is associated with excellent long-term disease-free survival 2-6. Excellent long-term survivorship of men with low-grade organ-localized PCa has focused attention on the high prevalence of sexual dysfunction, physical dysfunction, and chronic fatigue in this group, which contribute to impaired health-related quality of life (HRQOL) 7-12. The pathophysiology of these symptoms after radical prostatectomy is multifactorial, but androgen deficiency is a frequent and important remediable contributor 7-11,13-17
Androgen deficiency is common in men with prostate cancer who have undergone radical prostatectomy 11,14,15,18-21. Low libido, erectile dysfunction (ED), hot flashes, mobility limitation, decreased physical function, fatigue, and role limitations due to physical problems are major complaints of these men 7,8,22-27. Even with a bilateral nerve-sparing procedure, more than 50% develop sexual dysfunction after surgery 22,24,28,29.
Testosterone replacement therapy (TRT) improves corresponding symptoms in hypogonadal men without prostatic disease 30-34. Several large RCTs have established that TRT in older men with testosterone deficiency improves sexual activity, libido, erections, and satisfaction with intercourse 30-33. TRT reduces fatigue in HIV-infected men and a large 2016 randomized controlled trial reported improvements in energy following TRT 35,36 although some other trials did not find improvements in fatigue30. In young and middle-aged hypogonadal men, TRT has a positive impact on mood 34,37. Similar improvements in mood have been reported in older, hypogonadal, HIV-infected men 35,36. TRT also increases muscle mass and strength, aerobic capacity, and stair-climbing power 33,34,38-43. In older men, a meta-analysis of RCTs with TRT reported greater increments in lean mass, self-reported physical function, and stair climbing power44 while the reported improvement in gait speed has been small and less consistent 45-47
A history of PCa has been usually considered a contraindication for testosterone therapy 13. This guidance is based on observations that testosterone promotes the growth of metastatic prostate cancer, and that androgen deprivation therapy causes regression of metastatic PCa 48- 50. Therefore, many clinicians have reservations about administering TRT to PCa survivors.
However, the relationship between testosterone and PCa is complex 14-17. Epidemiologic studies have not revealed a consistent relationship between testosterone levels and PCa risk51- 53. Open-label trials and retrospective analyses have reported very low rates of disease recurrence in men treated with TRT after prostatectomy11,14-16. Even in men with high-grade prostatic intraepithelial neoplasia (HGPIN) – a group at potentially increased risk of developing PCa – TRT for one year did not increase PSA or rates of PCa54. However, these trials were neither randomized nor blinded. Men with Klinefelter Syndrome have lower mortality due to prostate cancer than the general population55. In Mendelian randomization studies, higher genetically-determined testosterone level has been associated with an increased lifetime risk of prostate cancer 56. Despite the absence of randomized trial data, the use of TRT to treat symptoms of androgen deficiency has continued to grow. Whether TRT is safe and efficacious in improving symptoms of testosterone deficiency in PCa survivors at low risk of recurrence is a high-priority question for these men and motivated this randomized clinical trial.
The primary objective of this trial is to determine whether TRT is safe and more efficacious in improving overall sexual activity than placebo in men who have undergone radical prostatectomy for organ-confined PCa, and have a low risk of recurrence and symptomatic androgen deficiency. Secondary objectives are to determine whether TRT is more efficacious than placebo in improving sexual desire, erectile function, distress associated with sexual dysfunction, sexual life quality, mood, energy, lean and fat mass, maximal voluntary strength, and physical function. Our primary hypothesis is that TRT will be safe and associated with greater improvements in overall sexual activity when compared to placebo. Our secondary hypothesis is that TRT will be associated with greater improvements in sexual desire, erectile function, distress associated with sexual dysfunction, sexual life quality, mood, energy, lean and fat mass, maximal voluntary strength, and performance-based as well as self-reported measures of physical function compared to placebo.
METHODS
Overall study design
This investigator-initiated proof-of-concept trial is a 12-week, randomized, placebo-controlled, double-blind parallel-group trial in 142 community-dwelling men, 40 years or older, with PCa who have undergone radical prostatectomy for organ-localized disease who have undetectable PSA for > 2 years after radical prostatectomy, and who have androgen deficiency and one or more symptoms of testosterone deficiency. The study is being conducted at the Brigham and Women’s Hospital (BWH) in Boston, USA, and the Johns Hopkins Medical Institutions in Baltimore, USA. The eligible participants are randomly assigned to receive testosterone cypionate 100 mg weekly or placebo injection weekly, stratified for age and use of phosphodiesterase 5 inhibitors (PDEIs). Efficacy outcomes are assessed at 6 and 12 weeks and include measures of sexual, physical, cognitive, and mood functions. Adverse event recording and safety laboratory tests, including PSA levels, are performed every 2 weeks during the study drug administration period. The length of the intervention was set to 12 weeks because the effects of TRT on sexual function, muscle mass, strength, well-being, and mood become apparent within 3 months; PSA rises within 3-4 weeks and reaches a plateau by 12 weeks57. Thus, a 3-month intervention duration is sufficient to detect meaningful changes in efficacy outcomes and PSA. The participants are followed for 3-months after the completion of the intervention period.
*Eligibility criteria
*Participant Recruitment
*Prospective Allocation of Study Participant
*Blinding
*Study Intervention
We chose testosterone cypionate for this trial because of its high bioavailability, ease of once-weekly administration, and predictable pharmacokinetics. All injections are administered by the study staff in the clinical research unit which ensures adherence. In a recent RCT of a high protein diet versus the recommended dietary allowances (RDA) with and without testosterone, this regimen of 100 mg testosterone cypionate weekly raised testosterone levels into the normal male range, and adherence with the regimen exceeded 99%. The control group receives weekly IM placebo injections.
*Study Outcomes
*Safety Assessment
*Defining Biochemical Recurrence
STATISTICAL CONSIDERATIONS
*Sample Size Determination
DATA ANALYSIS
*Descriptive analyses
*Analysis of the efficacy endpoints
*Safety Analyses
CURRENT STATUS
As of July 14, 2022, the trial had screened 1,562 persons on the telephone and 100 participants in-person. Of these 52 met the eligibility criteria and 43 were randomized. The first participant was randomized on May 13, 2019, and 30 participants completed the study procedures.
DISCUSSION
The SPIRIT Trial is the first placebo-controlled randomized trial of the efficacy and safety of TRT in prostate cancer survivors with symptoms of androgen deficiency and unequivocally low testosterone levels. Although a few open-label trials of TRT have been published, none was either randomized or placebo-controlled. The proposed RCT has many attributes of good trial design: concealed block randomization, the inclusion of placebo control, parallel-group design, attention to effect size and statistical power, and blinding. Testosterone thresholds for inclusion in previous open-label trials have varied across trials and many trials included men with normal or low normal testosterone levels, who would not be expected to improve with TRT. We will include men with unequivocally low testosterone levels and symptoms, consistent with the Endocrine Society's guidelines and the Institute of Medicine report. Recent large RCTs have shown that hypogonadal men, with symptoms and testosterone levels below these thresholds, are the most likely to respond to TRT. Because sexual symptoms are the most prevalent and important contributors to distress and impaired quality of life among men who have undergone radical prostatectomy and are at low cancer recurrence risk, we have included several validated measures of sexual function. Our primary outcome is overall sexual activity assessed using a validated psychosexual diary maintained over 7 consecutive days, but we have also included measures of sexual desire, erectile function, and distress due to sexual dysfunction. We have included self-reported measures of energy and function as well as performance-based measures of muscle performance and physical function that will be assessed by expert exercise physiologists using standardized procedures in the setting of a research laboratory. Additionally, we have included validated instruments for the evaluation of sexual function and energy that have been responsive to TRT in randomized trials of young and older hypogonadal men.
We have incorporated several measures to minimize risk, including the selection of men at low risk of disease recurrence, rigorous structured safety monitoring, pre-specified criteria for biochemical recurrence and stopping rules, and oversight by an independent DSMB.
Participant enrollment, a challenge in all clinical research studies, has been even more challenging due to several factors some of which are unique to this study population. Testosterone treatment has been deemed a contraindication in men with a history of prostate cancer in the guidelines of most professional societies. Unsurprisingly, many men with prostate cancer are hesitant to participate in a blinded clinical trial of testosterone treatment; many primary care providers share these concerns and are hesitant to refer their patients for the trial. The study enrollment in the trial started in March 2019. Due to the global COVID19 Pandemic, all clinical research activities were halted in the US in March 2020. After 7- months of a complete shutdown of non-Covid-related research, there was a gradual return to limited study activities until the reactivation of in-person study activities in early 2021. Participant recruitment in 2021 remained low due to the reluctance of middle-aged and older adults to come to the medical centers for research visits due to the fear of contracting the infection. Nevertheless, we have retained 89% of randomized participants in the study, and 97% of subjects who started the intervention adhered to all study procedures.
The trial's design should be viewed in the context of some limitations. There may be considerable heterogeneity in the baseline sexual function of the participants due to the type of prostatectomy they have received and this could also affect their response to the study intervention. We anticipate that randomization should result in balancing the distribution of baseline sexual function in the study arms. Some of the subjects with longstanding sexual dysfunction may not be sexually active and this may attenuate their response to the study intervention. The inclusion criteria did not consider drug-assisted IIEF scores. However, the randomization is stratified by PDE5I use and furthermore, the primary endpoint of change in sexual activity will be analyzed using mixed effects linear regression controlling for baseline and design effects including PDE5I use.
*The trial is neither large enough nor long enough to determine the risk of clinical cancer recurrence. Therefore, if the SPIRIT trial shows efficacy and short-term safety, that would provide the rationale for conducting larger, trials to establish the long-term safety of testosterone replacement therapy in this patient population.
Rodrigo J. Valderrábano, MD, MS; Karol Pencina, Ph.D.; Thomas W. Storer, Ph.D.; Kieran F. Reid Ph.D., MPH, Adam S. Kibel, MD, Arthur L. Burnett, MD; Grace Huang, MD, MS; Tanya Dorff, MD; Fabiola Privat, BS; Catherine Ghattas-Puylara, MPH; Lauren Wilson, RNP, Nancy K. Latham, Ph.D.; Mats Holmberg, MD Shalender Bhasin MB, BS
ABSTRACT
Background. Most men diagnosed with prostate cancer today have an organ-confined disease and a low risk of disease recurrence after radical prostatectomy. Testosterone deficiency in prostate cancer survivors contributes to impaired health-related quality of life but testosterone treatment is viewed as a contraindication in this population.
Objectives. We describe the design of the first randomized trial to determine the safety and efficacy of testosterone treatment in men who have undergone prostatectomy for nonaggressive prostate cancer and have symptomatic testosterone deficiency.
Methods. Surviving Prostate cancer while Improving the quality of life through Rehabilitation with Testosterone Trial (The SPIRIT Trial) is a randomized, placebo-controlled, double-blind, parallel-group trial in 142 men, >40 years, who have undergone radical prostatectomy for organ-confined prostate cancer, Gleason score <7 (3+4), Stage pT2, N0, M0 lesions and have symptomatic testosterone deficiency and undetectable PSA for >2 years after surgery. Eligible participants are randomized to weekly intramuscular injections of 100-mg testosterone cypionate or placebo for 12 weeks and followed for another 12 weeks. The primary endpoint is a change from baseline in sexual activity. Secondary outcomes include a change in sexual desire, erectile function, energy, lean and fat mass, and physical and cognitive performance. Safety is assessed by monitoring PSA, lower urinary tract symptoms, hemoglobin, and adverse events.
Results. The trial is being conducted at 2 trial sites in Boston, MA, and Baltimore, MD. As of July 30, 2022, 42 participants have been randomized. No PSA or clinical recurrence has been noted to date.
Discussion. Recruitment was slowed by COVID-19-related closures, a slow subsequent ramp-up of research activities, and patient concerns about the safety of testosterone treatment. Despite these challenges, participant retention has been high.
Conclusion. The SPIRIT Trial, a placebo-controlled, randomized trial, will determine whether testosterone replacement therapy is safe and efficacious in correcting symptoms of testosterone deficiency in prostate cancer survivors, and potentially inform clinical practice.
INTRODUCTION
Prostate cancer (PCa) is the most prevalent cancer in men worldwide 1. Most men diagnosed today with prostate cancer have a non-aggressive, organ-confined PCa and radical prostatectomy is associated with excellent long-term disease-free survival 2-6. Excellent long-term survivorship of men with low-grade organ-localized PCa has focused attention on the high prevalence of sexual dysfunction, physical dysfunction, and chronic fatigue in this group, which contribute to impaired health-related quality of life (HRQOL) 7-12. The pathophysiology of these symptoms after radical prostatectomy is multifactorial, but androgen deficiency is a frequent and important remediable contributor 7-11,13-17
Androgen deficiency is common in men with prostate cancer who have undergone radical prostatectomy 11,14,15,18-21. Low libido, erectile dysfunction (ED), hot flashes, mobility limitation, decreased physical function, fatigue, and role limitations due to physical problems are major complaints of these men 7,8,22-27. Even with a bilateral nerve-sparing procedure, more than 50% develop sexual dysfunction after surgery 22,24,28,29.
Testosterone replacement therapy (TRT) improves corresponding symptoms in hypogonadal men without prostatic disease 30-34. Several large RCTs have established that TRT in older men with testosterone deficiency improves sexual activity, libido, erections, and satisfaction with intercourse 30-33. TRT reduces fatigue in HIV-infected men and a large 2016 randomized controlled trial reported improvements in energy following TRT 35,36 although some other trials did not find improvements in fatigue30. In young and middle-aged hypogonadal men, TRT has a positive impact on mood 34,37. Similar improvements in mood have been reported in older, hypogonadal, HIV-infected men 35,36. TRT also increases muscle mass and strength, aerobic capacity, and stair-climbing power 33,34,38-43. In older men, a meta-analysis of RCTs with TRT reported greater increments in lean mass, self-reported physical function, and stair climbing power44 while the reported improvement in gait speed has been small and less consistent 45-47
A history of PCa has been usually considered a contraindication for testosterone therapy 13. This guidance is based on observations that testosterone promotes the growth of metastatic prostate cancer, and that androgen deprivation therapy causes regression of metastatic PCa 48- 50. Therefore, many clinicians have reservations about administering TRT to PCa survivors.
However, the relationship between testosterone and PCa is complex 14-17. Epidemiologic studies have not revealed a consistent relationship between testosterone levels and PCa risk51- 53. Open-label trials and retrospective analyses have reported very low rates of disease recurrence in men treated with TRT after prostatectomy11,14-16. Even in men with high-grade prostatic intraepithelial neoplasia (HGPIN) – a group at potentially increased risk of developing PCa – TRT for one year did not increase PSA or rates of PCa54. However, these trials were neither randomized nor blinded. Men with Klinefelter Syndrome have lower mortality due to prostate cancer than the general population55. In Mendelian randomization studies, higher genetically-determined testosterone level has been associated with an increased lifetime risk of prostate cancer 56. Despite the absence of randomized trial data, the use of TRT to treat symptoms of androgen deficiency has continued to grow. Whether TRT is safe and efficacious in improving symptoms of testosterone deficiency in PCa survivors at low risk of recurrence is a high-priority question for these men and motivated this randomized clinical trial.
The primary objective of this trial is to determine whether TRT is safe and more efficacious in improving overall sexual activity than placebo in men who have undergone radical prostatectomy for organ-confined PCa, and have a low risk of recurrence and symptomatic androgen deficiency. Secondary objectives are to determine whether TRT is more efficacious than placebo in improving sexual desire, erectile function, distress associated with sexual dysfunction, sexual life quality, mood, energy, lean and fat mass, maximal voluntary strength, and physical function. Our primary hypothesis is that TRT will be safe and associated with greater improvements in overall sexual activity when compared to placebo. Our secondary hypothesis is that TRT will be associated with greater improvements in sexual desire, erectile function, distress associated with sexual dysfunction, sexual life quality, mood, energy, lean and fat mass, maximal voluntary strength, and performance-based as well as self-reported measures of physical function compared to placebo.
METHODS
Overall study design
This investigator-initiated proof-of-concept trial is a 12-week, randomized, placebo-controlled, double-blind parallel-group trial in 142 community-dwelling men, 40 years or older, with PCa who have undergone radical prostatectomy for organ-localized disease who have undetectable PSA for > 2 years after radical prostatectomy, and who have androgen deficiency and one or more symptoms of testosterone deficiency. The study is being conducted at the Brigham and Women’s Hospital (BWH) in Boston, USA, and the Johns Hopkins Medical Institutions in Baltimore, USA. The eligible participants are randomly assigned to receive testosterone cypionate 100 mg weekly or placebo injection weekly, stratified for age and use of phosphodiesterase 5 inhibitors (PDEIs). Efficacy outcomes are assessed at 6 and 12 weeks and include measures of sexual, physical, cognitive, and mood functions. Adverse event recording and safety laboratory tests, including PSA levels, are performed every 2 weeks during the study drug administration period. The length of the intervention was set to 12 weeks because the effects of TRT on sexual function, muscle mass, strength, well-being, and mood become apparent within 3 months; PSA rises within 3-4 weeks and reaches a plateau by 12 weeks57. Thus, a 3-month intervention duration is sufficient to detect meaningful changes in efficacy outcomes and PSA. The participants are followed for 3-months after the completion of the intervention period.
*Eligibility criteria
*Participant Recruitment
*Prospective Allocation of Study Participant
*Blinding
*Study Intervention
We chose testosterone cypionate for this trial because of its high bioavailability, ease of once-weekly administration, and predictable pharmacokinetics. All injections are administered by the study staff in the clinical research unit which ensures adherence. In a recent RCT of a high protein diet versus the recommended dietary allowances (RDA) with and without testosterone, this regimen of 100 mg testosterone cypionate weekly raised testosterone levels into the normal male range, and adherence with the regimen exceeded 99%. The control group receives weekly IM placebo injections.
*Study Outcomes
*Safety Assessment
*Defining Biochemical Recurrence
STATISTICAL CONSIDERATIONS
*Sample Size Determination
DATA ANALYSIS
*Descriptive analyses
*Analysis of the efficacy endpoints
*Safety Analyses
CURRENT STATUS
As of July 14, 2022, the trial had screened 1,562 persons on the telephone and 100 participants in-person. Of these 52 met the eligibility criteria and 43 were randomized. The first participant was randomized on May 13, 2019, and 30 participants completed the study procedures.
DISCUSSION
The SPIRIT Trial is the first placebo-controlled randomized trial of the efficacy and safety of TRT in prostate cancer survivors with symptoms of androgen deficiency and unequivocally low testosterone levels. Although a few open-label trials of TRT have been published, none was either randomized or placebo-controlled. The proposed RCT has many attributes of good trial design: concealed block randomization, the inclusion of placebo control, parallel-group design, attention to effect size and statistical power, and blinding. Testosterone thresholds for inclusion in previous open-label trials have varied across trials and many trials included men with normal or low normal testosterone levels, who would not be expected to improve with TRT. We will include men with unequivocally low testosterone levels and symptoms, consistent with the Endocrine Society's guidelines and the Institute of Medicine report. Recent large RCTs have shown that hypogonadal men, with symptoms and testosterone levels below these thresholds, are the most likely to respond to TRT. Because sexual symptoms are the most prevalent and important contributors to distress and impaired quality of life among men who have undergone radical prostatectomy and are at low cancer recurrence risk, we have included several validated measures of sexual function. Our primary outcome is overall sexual activity assessed using a validated psychosexual diary maintained over 7 consecutive days, but we have also included measures of sexual desire, erectile function, and distress due to sexual dysfunction. We have included self-reported measures of energy and function as well as performance-based measures of muscle performance and physical function that will be assessed by expert exercise physiologists using standardized procedures in the setting of a research laboratory. Additionally, we have included validated instruments for the evaluation of sexual function and energy that have been responsive to TRT in randomized trials of young and older hypogonadal men.
We have incorporated several measures to minimize risk, including the selection of men at low risk of disease recurrence, rigorous structured safety monitoring, pre-specified criteria for biochemical recurrence and stopping rules, and oversight by an independent DSMB.
Participant enrollment, a challenge in all clinical research studies, has been even more challenging due to several factors some of which are unique to this study population. Testosterone treatment has been deemed a contraindication in men with a history of prostate cancer in the guidelines of most professional societies. Unsurprisingly, many men with prostate cancer are hesitant to participate in a blinded clinical trial of testosterone treatment; many primary care providers share these concerns and are hesitant to refer their patients for the trial. The study enrollment in the trial started in March 2019. Due to the global COVID19 Pandemic, all clinical research activities were halted in the US in March 2020. After 7- months of a complete shutdown of non-Covid-related research, there was a gradual return to limited study activities until the reactivation of in-person study activities in early 2021. Participant recruitment in 2021 remained low due to the reluctance of middle-aged and older adults to come to the medical centers for research visits due to the fear of contracting the infection. Nevertheless, we have retained 89% of randomized participants in the study, and 97% of subjects who started the intervention adhered to all study procedures.
The trial's design should be viewed in the context of some limitations. There may be considerable heterogeneity in the baseline sexual function of the participants due to the type of prostatectomy they have received and this could also affect their response to the study intervention. We anticipate that randomization should result in balancing the distribution of baseline sexual function in the study arms. Some of the subjects with longstanding sexual dysfunction may not be sexually active and this may attenuate their response to the study intervention. The inclusion criteria did not consider drug-assisted IIEF scores. However, the randomization is stratified by PDE5I use and furthermore, the primary endpoint of change in sexual activity will be analyzed using mixed effects linear regression controlling for baseline and design effects including PDE5I use.
*The trial is neither large enough nor long enough to determine the risk of clinical cancer recurrence. Therefore, if the SPIRIT trial shows efficacy and short-term safety, that would provide the rationale for conducting larger, trials to establish the long-term safety of testosterone replacement therapy in this patient population.
