Healthy
Conditions
Keywords
Healthy males Human volunteers pregabalin or placebo sperm quality and quantity
Brief summary
This study is being performed as a Phase IV FDA commitment study and is being powered adequately to assess changes in sperm concentration, FSH and testosterone in healthy male subjects treated with pregabalin as compared to placebo, in addition to confirming lack of effects on sperm motility.
Detailed description
This is a Phase 4 FDA commitment study. The purpose of the study is to evaluate the effects of pregabalin as compared to placebo on sperm concentration in healthy male subjects
Interventions
DRUGPregabalin
pregabalin 600 mg given twice a day
DRUGPlacebo
Placebo
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy 18 to 55 years old males
Exclusion criteria
* Screening sperm count \<20 x 106/mL; screening sperm motility \<50% motile (a+b) or \<25% Class a motile or screening sperm morphology \<30% normal or semen volume \<1.5 mL or white blood cell count \>1 x 106 /mL on any screening visit sample
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a 50 Percent (%) or More Reduction in Sperm Concentration From Baseline (Bsl) to End of Study (EOS) | Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26) | Baseline is the average of sperm concentrations from semen samples collected on or before Study Day 1. End of study is average of sperm concentrations from semen samples collected at end of washout period (Week 26) following 12 weeks of double-blind treatment. Mean sperm concentration (MSC) of a visit is average of the 2 sperm concentration samples collected at that visit. If sperm concentration was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead. Confidence intervals (CI) based on exact distribution. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 26 | Baseline, Week 26 (last observation in the Week 26 window) | FSH minimum normal range 1.4 IU/L to maximum normal range 18.1 IU/L. Week 26 was the non-missing value within 134 to 252 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 26 analysis. |
| Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 12 | Baseline, Week 12 (last observation in the Week 12 window) | FSH minimum normal range 1.4 IU/L to maximum normal range 18.1 IU/L. Week 12 was the last non-missing value within 2 to 133 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 12 analysis. |
| Change From Baseline in Testosterone to End of Study (EOS) | Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26) | End of study was the end of the washout period (Week 26) following 12 weeks of double-blind treatment. If the semen parameter was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead. |
| Change From Baseline in Testosterone to Week 26 | Baseline, Week 26 (last observation in the Week 26 window) | Week 26 was the non-missing value within 134 to 252 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 26 analysis. |
| Change From Baseline in Follicle Stimulating Hormone (FSH) to End of Study (EOS) | Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26) | FSH minimum normal range 1.4 International units per liter (IU/L) to maximum normal range 18.1 IU/L. End of study was the end of the washout period (Week 26) following 12 weeks of double-blind treatment. If the semen parameter was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead. |
| Change From Baseline in Sperm Motility to End of Study (EOS) | Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26) | Mean sperm motility (percent motility representing grade a+b \[a=sperm with progressive, straight-line motility; b=non-linear motility\]) was average of 2 samples collected at that visit. Normal value is ≥50% motility measured within 60 minutes of collection; higher values=greater percentage of sperm with motility. End of study was the end of the washout period (Week 26) following 12 weeks of double-blind treatment. If the semen parameter was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead. |
| Change From Baseline in Sperm Motility to Week 26 | Baseline, Week 26 (last observation in the Week 26 window) | Mean sperm motility (percent motility representing grade a+b) was the average of 2 samples collected at that visit. Normal value is ≥50% motility measured within 60 minutes of collection; higher values=greater percentage of sperm with motility. Week 26 was average of the last 2 values within window of 134 to 252 days from Study Day 1 and at least 1 of the 2 values was non-missing. If only 1 assessment date within the stated window, Week 26 was the value of that single assessment. If all values within window were missing, the records were not to be used for Week 26 analysis. |
| Change From Baseline in Sperm Motility to Week 12 | Baseline, Week 12 (last observation in the Week 12 window) | Mean sperm motility (percent motility representing grade a+b) was average of 2 samples collected at that visit. Normal value is ≥50% motility measured within 60 minutes of collection; higher values=greater percentage of sperm with motility. Week 12 was average of last 2 values within window of 2 to 133 days from Study Day 1 and at least 1 of the 2 values was non-missing. If there was only 1 assessment date within the stated window, then Week 12 was the value of that single assessment. If all the values within the window were missing, then the records were not to be used for Week 12 analysis. |
| Change From Baseline in Testosterone to Week 12 | Baseline, Week 12 (last observation in the Week 12 window) | Week 12 was the last non-missing value within 2 to 133 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 12 analysis. |
Countries
United States
Participant flow
Recruitment details
Study was conducted at 12 centers in the United States between February 2008 and February 2012; 903 participants were screened and 222 were assigned to study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin Pregabalin 50 mg PO BID starting dose with a 2-week titration followed by a fixed dose of 300 mg PO BID for 10 weeks, a 1 week taper at Week 12, and a 13 week washout period up to Week 26. | 111 |
| Placebo Placebo matching pregabalin treatment. | 109 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 |
| Overall Study | Discontinued after database release date | 1 | 0 |
| Overall Study | Entered, not randomized to treatment | 1 | 1 |
| Overall Study | Follow up after database release date | 1 | 0 |
| Overall Study | Lost to Follow-up | 7 | 10 |
| Overall Study | Other | 8 | 8 |
| Overall Study | Protocol Violation | 9 | 9 |
| Overall Study | Study terminated by sponsor | 3 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 9 |
Baseline characteristics
| Characteristic | Pregabalin | Placebo | Total |
|---|---|---|---|
| Age, Customized Between 18 and 44 years | 100 participants | 93 participants | 193 participants |
| Age, Customized Between 45 and 64 years | 11 participants | 16 participants | 27 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 111 Participants | 109 Participants | 220 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 111 | 18 / 109 |
| serious Total, serious adverse events | 0 / 111 | 0 / 109 |
Outcome results
Primary
Percentage of Participants With a 50 Percent (%) or More Reduction in Sperm Concentration From Baseline (Bsl) to End of Study (EOS)
Baseline is the average of sperm concentrations from semen samples collected on or before Study Day 1. End of study is average of sperm concentrations from semen samples collected at end of washout period (Week 26) following 12 weeks of double-blind treatment. Mean sperm concentration (MSC) of a visit is average of the 2 sperm concentration samples collected at that visit. If sperm concentration was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead. Confidence intervals (CI) based on exact distribution.
Time frame: Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26)
Population: Per protocol analysis set: all randomized participants who had ≥8 weeks of study treatment, sperm concentration measurements at or after week 12 window, did not discontinue for site violations, and did not have any major protocol violations. N=number of participants with analyzable data at observation; Last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin | Percentage of Participants With a 50 Percent (%) or More Reduction in Sperm Concentration From Baseline (Bsl) to End of Study (EOS) | 9.2 percentage of participants |
| Placebo | Percentage of Participants With a 50 Percent (%) or More Reduction in Sperm Concentration From Baseline (Bsl) to End of Study (EOS) | 3.2 percentage of participants |
Comparison: Study powered to show non-inferiority (NI) of pregabalin (PGB) to placebo (PBO) on the percentage of participants (N) with a ≥50% reduction in MSC from Bsl to end of washout (Week (Wk) 26, or last assessment on or after Wk 12 if Wk 26 not done). NI to be declared if upper bound of 95% CI for difference between PGB and PBO not \>20%. Assuming proportion of N with 50% reduction to be 6% for both groups, sample size N=65 per group would provide \>90% power to show NI of PGB to PBO.95% CI: [-2.29, 14.3]Confidence Interval Approach
Secondary
Change From Baseline in Follicle Stimulating Hormone (FSH) to End of Study (EOS)
FSH minimum normal range 1.4 International units per liter (IU/L) to maximum normal range 18.1 IU/L. End of study was the end of the washout period (Week 26) following 12 weeks of double-blind treatment. If the semen parameter was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead.
Time frame: Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26)
Population: Modified intent-to-treat (MITT) population included all randomized participants who received at least 1 dose of study medication (either pregabalin or placebo) and were not discontinued for major violation at the site level. N=number of participants with analyzable data at observation; LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Follicle Stimulating Hormone (FSH) to End of Study (EOS) | Baseline | 3.17 IU/L | Standard Deviation 1.624 |
| Pregabalin | Change From Baseline in Follicle Stimulating Hormone (FSH) to End of Study (EOS) | Change to EOS | 0.14 IU/L | Standard Deviation 0.746 |
| Placebo | Change From Baseline in Follicle Stimulating Hormone (FSH) to End of Study (EOS) | Baseline | 3.68 IU/L | Standard Deviation 1.997 |
| Placebo | Change From Baseline in Follicle Stimulating Hormone (FSH) to End of Study (EOS) | Change to EOS | 0.22 IU/L | Standard Deviation 0.953 |
p-value: 0.346295% CI: [-0.385, 0.136]ANCOVA
Secondary
Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 12
FSH minimum normal range 1.4 IU/L to maximum normal range 18.1 IU/L. Week 12 was the last non-missing value within 2 to 133 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 12 analysis.
Time frame: Baseline, Week 12 (last observation in the Week 12 window)
Population: MITT; N=number of participants with analyzable data at observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 12 | Baseline | 3.17 IU/L | Standard Deviation 1.624 |
| Pregabalin | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 12 | Change to Week 12 | -0.05 IU/L | Standard Deviation 0.785 |
| Placebo | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 12 | Baseline | 3.68 IU/L | Standard Deviation 1.997 |
| Placebo | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 12 | Change to Week 12 | 0.08 IU/L | Standard Deviation 0.974 |
p-value: 0.120495% CI: [-0.464, 0.054]ANCOVA
Secondary
Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 26
FSH minimum normal range 1.4 IU/L to maximum normal range 18.1 IU/L. Week 26 was the non-missing value within 134 to 252 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 26 analysis.
Time frame: Baseline, Week 26 (last observation in the Week 26 window)
Population: MITT population; N=number of participants (observed cases) with analyzable data at observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 26 | Change to Week 26 | 0.16 IU/L | Standard Deviation 0.757 |
| Pregabalin | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 26 | Baseline | 3.20 IU/L | Standard Deviation 1.685 |
| Placebo | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 26 | Baseline | 3.69 IU/L | Standard Deviation 2.05 |
| Placebo | Change From Baseline in Follicle Stimulating Hormone (FSH) to Week 26 | Change to Week 26 | 0.21 IU/L | Standard Deviation 0.949 |
p-value: 0.365295% CI: [-0.42, 0.156]ANCOVA
Secondary
Change From Baseline in Sperm Motility to End of Study (EOS)
Mean sperm motility (percent motility representing grade a+b \[a=sperm with progressive, straight-line motility; b=non-linear motility\]) was average of 2 samples collected at that visit. Normal value is ≥50% motility measured within 60 minutes of collection; higher values=greater percentage of sperm with motility. End of study was the end of the washout period (Week 26) following 12 weeks of double-blind treatment. If the semen parameter was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead.
Time frame: Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26)
Population: MITT; N=number of participants with analyzable data at observation; LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Sperm Motility to End of Study (EOS) | Baseline | 61.9 percent motility | Standard Deviation 9.98 |
| Pregabalin | Change From Baseline in Sperm Motility to End of Study (EOS) | Change to EOS | -3.2 percent motility | Standard Deviation 10.57 |
| Placebo | Change From Baseline in Sperm Motility to End of Study (EOS) | Baseline | 61.4 percent motility | Standard Deviation 8.32 |
| Placebo | Change From Baseline in Sperm Motility to End of Study (EOS) | Change to EOS | -1.8 percent motility | Standard Deviation 7.49 |
p-value: 0.409495% CI: [-3.645, 1.494]ANCOVA
Secondary
Change From Baseline in Sperm Motility to Week 12
Mean sperm motility (percent motility representing grade a+b) was average of 2 samples collected at that visit. Normal value is ≥50% motility measured within 60 minutes of collection; higher values=greater percentage of sperm with motility. Week 12 was average of last 2 values within window of 2 to 133 days from Study Day 1 and at least 1 of the 2 values was non-missing. If there was only 1 assessment date within the stated window, then Week 12 was the value of that single assessment. If all the values within the window were missing, then the records were not to be used for Week 12 analysis.
Time frame: Baseline, Week 12 (last observation in the Week 12 window)
Population: MITT; N=number of participants with analyzable data at observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Sperm Motility to Week 12 | Baseline | 61.95 percent motility | Standard Deviation 9.976 |
| Pregabalin | Change From Baseline in Sperm Motility to Week 12 | Change to Week 12 | -3.94 percent motility | Standard Deviation 8.57 |
| Placebo | Change From Baseline in Sperm Motility to Week 12 | Baseline | 61.38 percent motility | Standard Deviation 8.316 |
| Placebo | Change From Baseline in Sperm Motility to Week 12 | Change to Week 12 | -2.71 percent motility | Standard Deviation 8.186 |
p-value: 0.466695% CI: [-3.207, 1.477]ANCOVA
Secondary
Change From Baseline in Sperm Motility to Week 26
Mean sperm motility (percent motility representing grade a+b) was the average of 2 samples collected at that visit. Normal value is ≥50% motility measured within 60 minutes of collection; higher values=greater percentage of sperm with motility. Week 26 was average of the last 2 values within window of 134 to 252 days from Study Day 1 and at least 1 of the 2 values was non-missing. If only 1 assessment date within the stated window, Week 26 was the value of that single assessment. If all values within window were missing, the records were not to be used for Week 26 analysis.
Time frame: Baseline, Week 26 (last observation in the Week 26 window)
Population: MITT; N=number of participants with analyzable data at observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Sperm Motility to Week 26 | Baseline | 61.8 percent motility | Standard Deviation 10.46 |
| Pregabalin | Change From Baseline in Sperm Motility to Week 26 | Change to Week 26 | -2.6 percent motility | Standard Deviation 9.71 |
| Placebo | Change From Baseline in Sperm Motility to Week 26 | Baseline | 61.2 percent motility | Standard Deviation 8.71 |
| Placebo | Change From Baseline in Sperm Motility to Week 26 | Change to Week 26 | -1.8 percent motility | Standard Deviation 6.52 |
p-value: 0.906495% CI: [-2.649, 2.352]ANCOVA
Secondary
Change From Baseline in Testosterone to End of Study (EOS)
End of study was the end of the washout period (Week 26) following 12 weeks of double-blind treatment. If the semen parameter was not assessed at Week 26, then the last assessment on or after Week 12 (end of treatment) was used instead.
Time frame: Baseline, End of Study (last observation at Week 26 or last assessment on or after Week 12 if no data at Week 26)
Population: MITT; N=number of participants with analyzable data at observation; LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Testosterone to End of Study (EOS) | Baseline | 518.2 nanograms per deciliter (ng/dL) | Standard Deviation 179.13 |
| Pregabalin | Change From Baseline in Testosterone to End of Study (EOS) | Change to EOS | 10.4 nanograms per deciliter (ng/dL) | Standard Deviation 170.78 |
| Placebo | Change From Baseline in Testosterone to End of Study (EOS) | Baseline | 481.8 nanograms per deciliter (ng/dL) | Standard Deviation 171.07 |
| Placebo | Change From Baseline in Testosterone to End of Study (EOS) | Change to EOS | 0.8 nanograms per deciliter (ng/dL) | Standard Deviation 150.64 |
p-value: 0.287595% CI: [-20.999, 70.302]ANCOVA
Secondary
Change From Baseline in Testosterone to Week 12
Week 12 was the last non-missing value within 2 to 133 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 12 analysis.
Time frame: Baseline, Week 12 (last observation in the Week 12 window)
Population: MITT; N=number of participants with analyzable data at observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Testosterone to Week 12 | Baseline | 518.2 ng/dL | Standard Deviation 179.13 |
| Pregabalin | Change From Baseline in Testosterone to Week 12 | Change to Week 12 | -14.8 ng/dL | Standard Deviation 169.56 |
| Placebo | Change From Baseline in Testosterone to Week 12 | Baseline | 481.8 ng/dL | Standard Deviation 171.07 |
| Placebo | Change From Baseline in Testosterone to Week 12 | Change to Week 12 | 0.0 ng/dL | Standard Deviation 123.61 |
p-value: 0.795895% CI: [-52.804, 40.558]ANCOVA
Secondary
Change From Baseline in Testosterone to Week 26
Week 26 was the non-missing value within 134 to 252 days from Study Day 1. If there were multiple observations between the stated study days (all non-missing or a combination of missing and non-missing), then the latest non-missing value was selected for analysis. If all the values within the stated window were missing, then the records were not to be used for Week 26 analysis.
Time frame: Baseline, Week 26 (last observation in the Week 26 window)
Population: MITT; N=number of participants with analyzable data at observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Testosterone to Week 26 | Baseline | 517.9 ng/dL | Standard Deviation 182.34 |
| Pregabalin | Change From Baseline in Testosterone to Week 26 | Change to Week 26 | 13.8 ng/dL | Standard Deviation 171.37 |
| Placebo | Change From Baseline in Testosterone to Week 26 | Baseline | 474.6 ng/dL | Standard Deviation 167.09 |
| Placebo | Change From Baseline in Testosterone to Week 26 | Change to Week 26 | 2.6 ng/dL | Standard Deviation 146.8 |
p-value: 0.169995% CI: [-14.292, 80.158]ANCOVA