ORIGINAL ARTICLE
Pregabalin Does Not Affect Sperm Production in Healthy Volunteers: A Randomized, Double-blind, Placebo-controlled, Noninferiority Study Suresh C. Sikka, PhD, HCLD, CC*; Crystal Chen, MD†; Mary Almas, MS‡; Eugene Dula, MD§; Lloyd E. Knapp, PharmD†; Wayne J.G. Hellstrom, MD, FACS* *Department of Urology, Tulane University, New Orleans, Louisiana; †Pfizer Inc, Groton, Connecticut; ‡Pfizer Inc, New York, New York; §West Coast Clinical Research, Tarzana, California, U.S.A.
& Abstract Objective: The primary objective of this study was to compare the effects of pregabalin and placebo on sperm concentration in healthy male subjects. Changes in folliclestimulating hormone (FSH), testosterone, sperm motility, semen volume, and sperm morphology were also examined. Methods: This was a phase 4, multicenter, double-blind, randomized, placebo-controlled, noninferiority study. A 12week treatment period (placebo or 600 mg/day of pregabalin) was followed by a 1-week taper period and a 13-week washout period. The primary outcome measure was the percentage of subjects with a ≥ 50% reduction from baseline in sperm concentration at End of Study. Results: One hundred and nine subjects received placebo and 111 subjects received pregabalin. The difference between placebo and pregabalin with respect to the percentage of subjects with a ≥ 50% reduction from baseline in
Address correspondence and reprint requests to: Suresh C. Sikka, PhD, HCLD, CC, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112-2699, U.S.A. E-mail: [email protected]. Submitted: July 17, 2013; Accepted: November 27, 2013 DOI. 10.1111/papr.12171
© 2014 World Institute of Pain, 1530-7085/15/$15.00 Pain Practice, Volume 15, Issue 2, 2015 150–158
sperm concentration at End of Study was 6% (95% CI: 2.29 to 14.3%). Noninferiority of pregabalin compared to placebo was declared as the upper bound of the 95% CI was less than the prespecified noninferiority margin of 20%. There were no significant differences between placebo and pregabalin groups with respect to their effects on FSH, testosterone, or sperm motility. Changes in semen volume and sperm morphology were numerically similar in both treatment groups. Adverse events were consistent with the known safety profile of pregabalin. Treatment with 600 mg/day pregabalin for 12 weeks does not adversely affect spermatogenesis or serum levels of FSH and testosterone in healthy males. & Key Words: pregabalin, sperm production, noninferiority, multicenter clinical trial
INTRODUCTION Pregabalin is approved in the United States (US) for the treatment of neuropathic pain due to diabetic peripheral neuropathy, post-herpetic neuralgia, and spinal cord injury; for the treatment of fibromyalgia; and as an adjunct therapy for partial-onset seizures in adults.1 In the European Union, pregabalin is approved for the treatment of peripheral and central neuropathic pain; as an adjunctive therapy in adults with partial seizures; and
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for the treatment of generalized anxiety disorder.2 The actions of pregabalin are thought to be attributed to its binding at the a2d subunit of neuronal voltage-gated calcium channels and the resulting modulation of neurotransmitter release.3,4 In preclinical studies, pregabalin was associated with reversible effects on sperm parameters (decreased sperm count, decreased sperm motility, and increased sperm abnormalities) and reproductive function (reduced fertility and increased embryo loss) at approximately 3 times the maximum recommended human exposure of 600 mg/day.1 In a previous 12-week, randomized, parallel-group clinical trial in healthy male volunteers conducted prior to US approval, 600 mg/day pregabalin (N = 30) did not affect the primary outcome measure of sperm motility.1 Sperm morphology, semen volume, and sperm concentration were assessed as secondary measures. Although no detrimental effect on sperm concentration was observed, the previous study was not powered on the basis of sperm concentration. Therefore, the current randomized, double-blind, placebo-controlled, multicenter, phase 4 trial examined the effects of pregabalin on sperm production in healthy volunteers, with sperm concentration as the primary outcome measure. Specifically, the primary analysis tested the hypothesis that pregabalin is noninferior to placebo with respect to the proportion of subjects with a ≥ 50% decrease in sperm concentration. The study also evaluated sperm motility (total and progressive), sperm morphology, semen volume, and reproductive hormones as secondary measures.
METHODS The study was conducted from February 2008 to February 2012 at 12 centers in the US (ClinicialTrials.gov identifier: NCT00631696). The study was approved by the appropriate Institutional Review Board or Independent Ethics Committee at each participating investigational center, and all subjects provided written informed consent before entering the study. This study was conducted in compliance with the Declaration of Helsinki and all International Conference on Harmonization Good Clinical Practice Guidelines.
result for illicit drugs; were willing to avoid recreational substance use during the trial; and were willing to refrain from all sexual activity for 48 hours prior to providing semen samples. Key exclusion criteria at screening included abnormal follicle-stimulating hormone (FSH) or testosterone levels; evidence of hypogonadism, gynecomastia, varicocele, or spermatocele; sperm count < 20 9 106/mL; progressive sperm motility < 50% motile (grade a + b) or < 25% class A motile5; sperm morphology < 30% normal; semen volume < 1.5 mL; or white blood cell count > 1.0 9 106/mL (leukocytospermia). Concurrent hormone or hormone-like (nutraceuticals) therapy was not allowed during the study. Use of any medication to treat erectile disorder or use of any prescription medication for the treatment of cardiovascular, hematologic, hepatic, renal, metabolic, gastrointestinal, neurologic, or reproductive tract problems was also prohibited. Androgenic, gonadotropic, and gonadotoxic medications (eg, marijuana, radiation therapy, chemotherapeutic agents) were not allowed during the study and must have been discontinued at least 84 days prior to randomization. Study Design The study was composed of 5 phases: a 2-week screening period; a 2-week, double-blind, dose-titration period; a 10-week, double-blind, fixed-dose period; a 1week, double-blind, taper period; and a 13-week washout period (Figure 1). Eligible subjects were randomized in a double-blinded manner to receive pregabalin or matching placebo in a 1:1 ratio according to a computer-generated, pseudorandom code using the method of random permuted blocks. This centralized telerandomization system was also used to allocate treatment in a double-blinded manner, and both pregabalin and placebo were identical in appearance in order to preserve blinding. Treatment compliance was based on returned capsule counts at each visit. Subjects who missed ≥ 7 consecutive days of treatment were considered noncompliant and, potentially, discontinued from the trial. Treatment and Assessment Schedule
Entry Criteria Healthy male volunteers aged 18 to 55 years and weighing ≥ 50 kg were eligible for the study. In addition, subjects must have had a negative urine screen
Randomized subjects initially received oral pregabalin, or matching placebo, at a dose of 100 mg/day (50 mg twice daily) for 2 weeks. The dose of pregabalin was then increased to 600 mg/day (300 mg twice daily) for
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600 mg/day
100 mg/day 0 mg/day Screening Titration
Fixed dose
Taper
Washout
Weeks –2
Semen analysis
0
2
Semen analysis
12
13
Semen analysis
26
Semen analysis
Figure 1. Trial design. All dosing was twice a day: 100 mg/day = 50 mg 9 2; 600 mg/day = 300 mg 9 2. If subjects could not tolerate 600 mg/day, they received 450 mg/day. If subjects could not tolerate 450 mg/day, they were discontinued from the study.
10 additional weeks. Subjects who could not tolerate 600 mg/day were reduced, at the discretion of the investigator, to 450 mg/day for the remainder of the study. Subjects who could not tolerate 450 mg/day were discontinued from the study. Two semen samples were collected (48 to 96 hours apart) at screening, baseline (Week 0), end of treatment (Week 12), and after the washout period (Week 26). All semen evaluations at participating sites were performed in a standardized manner by technicians who were trained and certified at a central facility to ensure minimal technical variation. Analysis Sets Two different analyses sets were utilized in this study: as per protocol (PP) and modified intent-to-treat (mITT) populations. The PP population included all randomized subjects who received ≥ 8 weeks of study treatment, had 2 sperm concentration measurements at Week 12 and/or Week 26, did not discontinue due to site violations, and did not have any major protocol violations. The mITT population included all randomized subjects who received ≥ 1 dose of study medication and were not discontinued for a major protocol violation at the site level. Timepoints Three different timepoints were analyzed in this study: End of Study, Week 26, and Week 12. They differed
with respect to how missing subject data were handled. For the End of Study analysis, Week 26 data were used. However, if a subject was missing Week 26 data, the subject’s Week 12 data were included in the analysis. For the Week 26 analysis, only Week 26 data were used. If Week 26 data were missing, that subject was excluded from the analysis. For the Week 12 analysis, only Week 12 data were used. If Week 12 data were missing, that subject was excluded from the analysis. In the PP population, sperm concentration was based on the average of 2 semen samples taken 48 to 96 hours apart. If 1 of the 2 samples was missing at a particular timepoint, then the subject was excluded from analysis at that particular timepoint. In the PP population, Weeks 12 and 26 were defined as 70 to 98 and 168 to 196 days from study Day 1, respectively. In the mITT population, only 1 of 2 semen samples was necessary for inclusion in an analysis at a particular timepoint. In the mITT population, Weeks 12 and 26 were defined as 2 to 133 and 134 to 252 days from study Day 1, respectively. Outcome Measures The primary outcome measure (and basis for samplesize determination) was the proportion of subjects with a ≥ 50% reduction in sperm concentration from baseline to End of Study. The threshold of ≥ 50% greater reduction was chosen to allow for normal variations in
Pregabalin’s Lack of Effect on Sperm Production 153
sperm concentration within and between individuals.6–9 Secondary outcome measures included the change in serum FSH, serum testosterone, and sperm motility at End of Study, Week 26, and Week 12. Sperm morphology and semen volume were assessed at baseline, Week 12, and Week 26. Statistical Analysis The primary analysis tested the hypothesis that pregabalin is noninferior (no worse than) to placebo with respect to the proportion of subjects with a ≥ 50% decrease in sperm concentration. This analysis was performed in the PP population using End of Study data. Noninferiority of pregabalin, compared with placebo, was declared if the upper bound of the 2-sided 95% confidence interval (CI) for the difference between the 2 treatment groups was less than the prespecified margin of 20%.10–13 It was assumed that the proportion of subjects with a 50% reduction in sperm concentration would be 6% for both groups. Therefore, a sample size of 65 subjects per treatment group would provide > 90% power to show noninferiority of pregabalin to placebo. In order to account for subject discontinuations and protocol violations, 110 and 112 subjects were randomized to receive placebo and pregabalin, respectively. To support the primary analysis described above (PP population at End of Study), secondary analyses of the proportion of subjects with ≥ 50% reduction in sperm concentration were conducted at End of Study, Week 26, and Week 12 in the mITT population. Least squares mean changes in serum hormones (FSH and testosterone) and sperm motility at End of Study, Week 26, and Week 12 in the mITT population were analyzed using analysis of covariance (ANCOVA) with treatment and center as factors and baseline values as covariate in the model. All tests were performed at the 2-sided 5% significance level (P = 0.05). Mean changes in sperm morphology and semen volume at Weeks 12 and 26 were summarized descriptively in the mITT population, and no inferential testing was performed. Safety Measures The safety profile of pregabalin was assessed based on observed and reported adverse events (AEs), which were evaluated by the investigator for severity and relationship to study treatment. Additional safety
measurements included physical examinations and clinical laboratory tests. All subjects who received ≥ 1 dose of study treatment were in the safety analysis.
RESULTS A total of 222 subjects were randomized, 109 received placebo and 111 received pregabalin (Figure 2). Subject demographics were similar between treatment groups (Table 1). Median treatment duration was 92 and 90 days in the placebo and pregabalin groups, respectively. More than 75% of subjects in the pregabalin group received treatment for 70 to 98 days. A majority of pregabalin-treated subjects received a final dose of 600 mg/day (n = 100, 90%). The most frequently reported concomitant drug treatments were multivitamins (placebo: n = 6; pregabalin: n = 6) and ibuprofen (placebo: n = 5; pregabalin: n = 6). The proportion of subjects in the PP population who experienced a ≥ 50% reduction in sperm concentration at End of Study was 3.2% (n = 2) in the placebo group and 9.2% (n = 6) in the pregabalin group (Table 2). The upper bound of the 95% CI for the treatment difference between pregabalin and placebo was 14.30%, which was less than the prespecified noninferiority margin of 20%. Thus, pregabalin was not inferior to placebo with respect to the proportion of subjects who experienced a ≥ 50% reduction in sperm concentration at End of Study (Figure 3). This finding is supported by secondary analyses in the mITT population at End of Study (upper bound of 95% CI = 10.50%), Week 26 (upper bound = 12.33%), and Week 12 (upper bound = 6.87%; Table 2 and Figure 3). Pregabalin treatment increased FSH levels, compared with baseline, at End of Study (+ 0.39 IU/L), Week 26 (+ 0.10 IU/L), and Week 12 (+ 0.29 IU/L). However, these changes were small and not significantly different from placebo (Table 3). Likewise, pregabalin-mediated changes in testosterone levels at End of Study (+ 1.17 ng/dL), Week 26 (+ 2.28 ng/dL), and Week 12 ( 12.85 ng/dL) were minor and not significantly different from placebo (Table 3). Sperm motility was also decreased in the pregabalin group compared to baseline but, again, these changes were small and not significantly different from placebo; the percentage of subjects with grade a + b motility decreased by 3.98% at End of Study, 3.82% at Week 26, and 3.73% at Week 12 (Table 3). Although no inferential statistical testing was performed, there appeared to be no difference between
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Screened (n=903)
Randomized to placebo (n=110)
Randomized to pregabalin (n=112)
Treated (n=109)
Treated (n=111)
Discontinued: 39 (35.8%) Lost to follow-up: 10 (9.2%) No longer willing to participate: 9 (8.3%) Protocol violation: 9 (8.3%) Adverse event: 0 Study terminated by sponsor: 3 (2.8%) Other: 8 (7.3%)
Discontinued: 34 (30.6%) Lost to follow-up: 7 (6.3%) No longer willing to participate: 2 (1.8%) Protocol violation: 9 (8.1%) Adverse event: 5 (4.5%) Study terminated by sponsor: 3 (2.7%) Other: 8 (7.2%)
Ongoing: 2 (1.8%)a
Ongoing: 0
Completed: 70/109 64.2%
Completed: 75/111 67.6%
Semen analysis PP: 62 (56.9%) mITT: 88 (80.7%)
Semen analysis PP: 65 (58.6%) mITT: 90 (81.1%)
Safety analysis: 109 (100%)
Safety analysis: 111 (100%)
Figure 2. Subject disposition. aAt time of database release, 2 subjects in the pregabalin treatment group were classified as “ongoing” due to delayed collection of subject summary page. Both subjects completed treatment. mITT, modified intention to treat; PP, per protocol.
Table 1. Subject Demographics Number (%) of Subjects
Age, years Mean (SD) Range Race, % White Black Asian Other Weight, kg Mean (SD) Range Height, cm Mean (SD) Range SD, standard deviation.
Placebo (n = 109)
Pregabalin (n = 111)
32.1 (9.4) 19 to 55
31.1 (9.0) 18 to 52
84 (77.1) 14 (12.8) 5 (4.6) 6 (5.5)
85 (76.6) 14 (12.6) 5 (4.5) 7 (6.3)
89.3 (20.7) 44.9 to 195.5
89.2 (18.8) 52.6 to 158.7
178.5 (8.2) 147.0 to 203.0
178.7 (7.5) 160.0 to 206.0
pregabalin and placebo groups with respect to sperm morphology or semen volume at Weeks 12 or 26 (Table 4). AEs were reported more frequently in the pregabalin group compared with placebo (Table 5). A majority of all AEs were mild (78.9%), and there were no severe AEs associated with pregabalin treatment. There were no serious AEs in either treatment group. Few subjects (< 5%) discontinued due to an AE or had a temporary discontinuation/dose-reduction due to an AE (< 9%). The most common treatment-related AEs in the pregabalin group were dizziness, somnolence, euphoric mood, fatigue, and paresthesia. There were no clinically significant changes related to laboratory tests, vital signs, or physical examinations.
Pregabalin’s Lack of Effect on Sperm Production 155
Table 2. Percentage of Subjects with ≥ 50% Reduction in Mean Sperm Concentration from Baseline Placebo PP end of study, N Subjects with ≥ 50% mITT end of study, N Subjects with ≥ 50% mITT Week 26, N Subjects with ≥ 50% mITT Week 12, N Subjects with ≥ 50%
decrease, n (%) decrease, n (%) decrease, n (%) decrease, n (%)
62 2 72 5 60 3 72 7
(3.2) (6.9) (5.0) (9.7)
Pregabalin 65 6 79 7 69 6 79 6
(9.2) (8.9) (8.7) (7.6)
PP, per protocol; mITT, modified intention to treat.
Pregabalin non-inferior to placebo
Table 3. Mean Change in FSH, Testosterone, and Sperm Motility from Baseline*
Pregabalin inferior to placebo
miTT Week 12 miTT Week 26 miTT End of Study PP End of Study
–20 –10 0 10 20 30 Percent difference between pregabalin and placebo
Figure 3. Treatment difference between pregabalin and placebo. Data shown are mean 95% confidence interval. The prespecified noninferiority margin of 20% is shown as a vertical dashed line. mITT, modified intention to treat; PP, per protocol.
DISCUSSION This phase 4, double-blind, randomized, placebo-controlled, multicenter study demonstrates that treatment with 600 mg/day pregabalin for 12 weeks has no significant effects on sperm production in healthy men aged 18 to 55 years. Pregabalin was not inferior to placebo with respect to the proportion of subjects with ≥ 50% reduction in sperm concentration at End of Study. The benchmark of ≥ 50% reduction in sperm concentration has been used in previous noninferiority studies10,12,13 and was chosen to account for normal physiological variations in sperm production.6–9 The primary analysis of sperm concentration was based on End of Study data. This means that, ideally, semen samples were collected and analyzed after subjects had undergone 12 weeks of pregabalin treatment (1 full spermatogenesis cycle) and 13 weeks of taper/washout (another full spermatogenesis cycle).14 This endpoint was based on discussions with the US
Placebo FSH, IU/L End of study N LS mean LS mean difference† 95% CI P value‡ Week 26 N LS mean LS mean difference† 95% CI P value‡ Week 12 N LS mean LS mean difference† 95% CI P value‡ Testosterone, ng/dL End of study N LS mean LS mean difference† 95% CI P value‡ Week 26 N LS mean LS mean difference† 95% CI P value‡ Week 12 N LS mean LS mean difference† 95% CI P value‡ Sperm motility,%§ End of study N LS mean LS mean difference‡ 95% CI P value‡ Week 26 N LS mean LS mean difference† 95% CI P value‡ Week 12 N LS mean LS mean difference† 95% CI P value‡
Pregabalin
72 0.51 – – –
79 0.39 0.12 ( 0.39, 0.14) 0.35
60 0.23 – – –
69 0.1 0.13 ( 0.42, 0.16) 0.37
72 0.5 – – –
79 0.29 0.2 ( 0.46, 0.05) 0.12
72 23.48 – – –
79 1.17 24.65 ( 21.00, 70.30) 0.29
60 30.65 – – –
69 2.28 32.93 ( 14.29, 80.16) 0.17
72 6.72 – – –
79 12.85 6.12 ( 52.80, 40.56) 0.8
73 2.9 – – –
79 3.98 1.08 ( 3.65, 1.49) 0.41
60 3.67 – – –
69 3.82 0.15 ( 2.65, 2.35) 0.91
73 2.87 – – –
79 3.73 0.86 ( 3.21, 1.48) 0.47
*Based on the modified intention-to-treat population. † Pregabalin – placebo. ‡ Versus placebo. § Grade a + b. Higher values indicate greater progressive motility. FSH, follicle-stimulating hormone; LS, least squares; CI, confidence interval.
Food and Drug Administration and with the rationale that the full effect of pregabalin exposure would be evident in the spermatogenesis cycle (12 to 13 weeks)
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Table 4. Summary of Semen Volume and Sperm Morphology*
Semen volume, mL Baseline N Mean (SD) Week 12 N Mean (SD) Week 26 N Mean (SD) Normal sperm morphology†,% Baseline N Mean (SD) Week 12 N Mean (SD) Week 26 N Mean (SD)
Placebo
Pregabalin
88 2.56 (1.02)
90 2.98 (1.14)
73 2.52 (1.08)
79 3.09 (1.55)
60 2.45 (0.98)
69 2.89 (1.13)
88 44.39 (7.39)
90 45.34 (6.33)
72 44.58 (6.32)
79 44.08 (6.30)
60 44.48 (7.53)
69 44.79 (6.76)
*Based on the modified intention-to-treat population. †Refers to the percentage of sperm with normal head. SD, standard deviation.
Table 5. Summary of Adverse Events, Number (%) of Subjects All Causalities
Number of AEs Subjects with an AE Subjects with a SAE Subjects with a severe AE Subjects discontinuations due to an AE Subjects with dose reductions or temporary discontinuation due to an AE Common AEs* Dizziness Somnolence Euphoric mood Fatigue Headache Muscle strain Paresthesia Nausea
Treatment-related
Placebo (n = 109)
Pregabalin (n = 111)
Placebo (n = 109)
Pregabalin (n = 111)
70 45 (41.3)
148 61 (55.0)
31 21 (19.3)
100 48 (43.2)
0
0
0
0
2 (1.8)
1 (0.9)
1 (0.9)
0
0
5 (4.5)
0
5 (4.5)
0
9 (8.1)
0
8 (7.2)
1 5 1 1 5 1 1 4
(0.9) (4.6) (0.9) (0.9) (4.6) (0.9) (0.9) (3.7)
21 11 6 5 4 4 4 2
(18.9) (9.9) (5.4) (4.5) (3.6) (3.6) (3.6) (1.8)
1 5 1 1 4 0 0 4
(0.9) (4.6) (0.9) (0.9) (3.7)
(3.7)
20 11 6 5 3 0 4 1
(18.0) (9.9) (5.4) (4.5) (2.7) (3.6) (0.9)
*Occurring in ≥ 3% of subjects. AE, adverse event; SAE, serious adverse event.
after discontinuation of treatment. To support the primary analysis, the proportion of subjects with ≥ 50% reduction in sperm concentration was also
analyzed in the mITT at End of Study, Week 26, and Week 12. In all cases, pregabalin was not inferior to placebo. These data demonstrate that pregabalin does not affect the spermatogenesis cycle that occurs concurrent to treatment (Week 12 data), nor the spermatogenesis that follows discontinuation of treatment (Week 26 and End of Study data). A total of 8 subjects (pregabalin = 6, placebo = 2) had a ≥ 50% reduction in sperm concentration at Week 26. However, for 7 of these subjects, changes in sperm concentration reverted to less than 50% after a 3-month (1 spermatogenesis cycle) follow-up period. Men who have low sperm concentration often also have abnormal sperm motility and morphology.15,16 In the current study, pregabalin treatment was not associated with any significant effect on progressive motility or total sperm motility compared with placebo. This was evident immediately following cessation of treatment at Week 12 and following the washout period at Week 26. Although no inferential statistical testing was performed, sperm morphology and semen volume were also numerically similar between pregabalin and placebo groups following both the treatment (Week 12) and washout (Week 26) periods. Additionally, pregabalin treatment was not associated with any significant change in the serum concentration of the reproductive hormones, FSH or testosterone. These findings are broadly consistent with a previous randomized, controlled trial of the effects of pregabalin on reproductive parameters in healthy male volunteers (unpublished data; Pfizer protocol 1008-072). In this previous study, which was powered to examine pregabalin’s effect on sperm motility, 30 subjects received 600 mg/day pregabalin for 3 months. The difference between placebo- and pregabalin-treated subjects, with respect to the percentage of sperm with normal motility, was < 4%; the percentage of motile sperm did not change more than 2% from baseline in either treatment group. The previous trial also examined sperm morphology, semen volume, and sperm concentration as secondary endpoints and, as in the current trial, no significant differences between placebo and pregabalin treatment were reported. The dose of 600 mg/day was chosen in the current trial and in the previous trial, because it is the maximum recommended daily dose of pregabalin.1 This dose of pregabalin was well-tolerated in healthy subjects in this study. Nearly 80% of all AEs were mild in severity and only < 5% of subjects in the pregabalin group discontinued treatment due to an AE. Furthermore, the AE
Pregabalin’s Lack of Effect on Sperm Production 157
profile in these subjects was similar to the known profile for pregabalin. A potential limitation of multicenter sperm studies could be variability in semen analysis. However, such variability was taken into account during design of the study and was closely controlled by following standardized techniques for the evaluation of semen volume, sperm concentration, and sperm motility. These evaluations were performed by a trained and certified laboratory technician at each participating site. In addition, sperm morphology slides were prepared by trained site technicians according to a standardized protocol, and the evaluations were conducted at a central facility by a central reader, thus ensuring minimal technical variation. Another potential limitation is the inability to extrapolate our findings to other populations, such as healthy men < 18 or > 55 years of age or men with abnormal semen parameters. Finally, subjects in the current study were treated with pregabalin for 12 weeks (only 1 spermatogenesis cycle), and thus, we cannot extrapolate our findings beyond this treatment duration. Overall, our findings demonstrate that treatment with 600 mg/day pregabalin for 12 weeks does not adversely affect spermatogenesis, as well as serum levels of FSH and testosterone in healthy males.
DISCLOSURES The preliminary study data was presented by Dr. Sikka at the 10th International Congress of Andrology in Melbourne, Australia, 23 to 26 February, 2013 (Andrology, 2013, suppl 1, 99). S. Sikka received standardized semen analysis training and centralized morphology slide reading contracts from Pfizer for this study. E. Dula has served as a clinical research investigator for Repros Therapeutics, Allergan, Nymox Pharmaceutical, Serenity Pharmaceuticals, Boehringer Ingelheim, Pfizer and Endo Pharmaceuticals. W. Hellstrom serves or has served as a consultant/advisor to American Medical Systems, Andromedical, Auxilium, Allergan, Coloplast, Cook, Endo, Johnson & Johnson, Lilly U.S.A., Slate Pharmaceutical, and Vivus; has been a meeting participant or lecturer on behalf of Auxilium, Cook, Endo, Johnson & Johnson, Lilly U.S.A., Slate Pharmaceutical, and Vivus; has acted as an investigator in a study or trial for Auxilium, Allergan, Coloplast, Endo, Johnson & Johnson, Slate Pharmaceutical, and Vivus; and serves as a board member, officer, or trustee for Theralogix and the National
Institutes of Health. C. Chen, M. Almas, and L. Knapp are full-time employees of, and hold stock in, Pfizer Inc. This study was sponsored by Pfizer Inc. Medical writing support was provided by Matt Soulsby, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc.
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Pregabalin Does Not Affect Sperm Production in Healthy Volunteers: A Randomized, Double-blind, Placebo-controlled, Noninferiority Study Suresh C. Sikka, PhD, HCLD, CC*; Crystal Chen, MD†; Mary Almas, MS‡; Eugene Dula, MD§; Lloyd E. Knapp, PharmD†; Wayne J.G. Hellstrom, MD, FACS* *Department of Urology, Tulane University, New Orleans, Louisiana; †Pfizer Inc, Groton, Connecticut; ‡Pfizer Inc, New York, New York; §West Coast Clinical Research, Tarzana, California, U.S.A.
& Abstract Objective: The primary objective of this study was to compare the effects of pregabalin and placebo on sperm concentration in healthy male subjects. Changes in folliclestimulating hormone (FSH), testosterone, sperm motility, semen volume, and sperm morphology were also examined. Methods: This was a phase 4, multicenter, double-blind, randomized, placebo-controlled, noninferiority study. A 12week treatment period (placebo or 600 mg/day of pregabalin) was followed by a 1-week taper period and a 13-week washout period. The primary outcome measure was the percentage of subjects with a ≥ 50% reduction from baseline in sperm concentration at End of Study. Results: One hundred and nine subjects received placebo and 111 subjects received pregabalin. The difference between placebo and pregabalin with respect to the percentage of subjects with a ≥ 50% reduction from baseline in
Address correspondence and reprint requests to: Suresh C. Sikka, PhD, HCLD, CC, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112-2699, U.S.A. E-mail: [email protected]. Submitted: July 17, 2013; Accepted: November 27, 2013 DOI. 10.1111/papr.12171
© 2014 World Institute of Pain, 1530-7085/15/$15.00 Pain Practice, Volume 15, Issue 2, 2015 150–158
sperm concentration at End of Study was 6% (95% CI: 2.29 to 14.3%). Noninferiority of pregabalin compared to placebo was declared as the upper bound of the 95% CI was less than the prespecified noninferiority margin of 20%. There were no significant differences between placebo and pregabalin groups with respect to their effects on FSH, testosterone, or sperm motility. Changes in semen volume and sperm morphology were numerically similar in both treatment groups. Adverse events were consistent with the known safety profile of pregabalin. Treatment with 600 mg/day pregabalin for 12 weeks does not adversely affect spermatogenesis or serum levels of FSH and testosterone in healthy males. & Key Words: pregabalin, sperm production, noninferiority, multicenter clinical trial
INTRODUCTION Pregabalin is approved in the United States (US) for the treatment of neuropathic pain due to diabetic peripheral neuropathy, post-herpetic neuralgia, and spinal cord injury; for the treatment of fibromyalgia; and as an adjunct therapy for partial-onset seizures in adults.1 In the European Union, pregabalin is approved for the treatment of peripheral and central neuropathic pain; as an adjunctive therapy in adults with partial seizures; and
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for the treatment of generalized anxiety disorder.2 The actions of pregabalin are thought to be attributed to its binding at the a2d subunit of neuronal voltage-gated calcium channels and the resulting modulation of neurotransmitter release.3,4 In preclinical studies, pregabalin was associated with reversible effects on sperm parameters (decreased sperm count, decreased sperm motility, and increased sperm abnormalities) and reproductive function (reduced fertility and increased embryo loss) at approximately 3 times the maximum recommended human exposure of 600 mg/day.1 In a previous 12-week, randomized, parallel-group clinical trial in healthy male volunteers conducted prior to US approval, 600 mg/day pregabalin (N = 30) did not affect the primary outcome measure of sperm motility.1 Sperm morphology, semen volume, and sperm concentration were assessed as secondary measures. Although no detrimental effect on sperm concentration was observed, the previous study was not powered on the basis of sperm concentration. Therefore, the current randomized, double-blind, placebo-controlled, multicenter, phase 4 trial examined the effects of pregabalin on sperm production in healthy volunteers, with sperm concentration as the primary outcome measure. Specifically, the primary analysis tested the hypothesis that pregabalin is noninferior to placebo with respect to the proportion of subjects with a ≥ 50% decrease in sperm concentration. The study also evaluated sperm motility (total and progressive), sperm morphology, semen volume, and reproductive hormones as secondary measures.
METHODS The study was conducted from February 2008 to February 2012 at 12 centers in the US (ClinicialTrials.gov identifier: NCT00631696). The study was approved by the appropriate Institutional Review Board or Independent Ethics Committee at each participating investigational center, and all subjects provided written informed consent before entering the study. This study was conducted in compliance with the Declaration of Helsinki and all International Conference on Harmonization Good Clinical Practice Guidelines.
result for illicit drugs; were willing to avoid recreational substance use during the trial; and were willing to refrain from all sexual activity for 48 hours prior to providing semen samples. Key exclusion criteria at screening included abnormal follicle-stimulating hormone (FSH) or testosterone levels; evidence of hypogonadism, gynecomastia, varicocele, or spermatocele; sperm count < 20 9 106/mL; progressive sperm motility < 50% motile (grade a + b) or < 25% class A motile5; sperm morphology < 30% normal; semen volume < 1.5 mL; or white blood cell count > 1.0 9 106/mL (leukocytospermia). Concurrent hormone or hormone-like (nutraceuticals) therapy was not allowed during the study. Use of any medication to treat erectile disorder or use of any prescription medication for the treatment of cardiovascular, hematologic, hepatic, renal, metabolic, gastrointestinal, neurologic, or reproductive tract problems was also prohibited. Androgenic, gonadotropic, and gonadotoxic medications (eg, marijuana, radiation therapy, chemotherapeutic agents) were not allowed during the study and must have been discontinued at least 84 days prior to randomization. Study Design The study was composed of 5 phases: a 2-week screening period; a 2-week, double-blind, dose-titration period; a 10-week, double-blind, fixed-dose period; a 1week, double-blind, taper period; and a 13-week washout period (Figure 1). Eligible subjects were randomized in a double-blinded manner to receive pregabalin or matching placebo in a 1:1 ratio according to a computer-generated, pseudorandom code using the method of random permuted blocks. This centralized telerandomization system was also used to allocate treatment in a double-blinded manner, and both pregabalin and placebo were identical in appearance in order to preserve blinding. Treatment compliance was based on returned capsule counts at each visit. Subjects who missed ≥ 7 consecutive days of treatment were considered noncompliant and, potentially, discontinued from the trial. Treatment and Assessment Schedule
Entry Criteria Healthy male volunteers aged 18 to 55 years and weighing ≥ 50 kg were eligible for the study. In addition, subjects must have had a negative urine screen
Randomized subjects initially received oral pregabalin, or matching placebo, at a dose of 100 mg/day (50 mg twice daily) for 2 weeks. The dose of pregabalin was then increased to 600 mg/day (300 mg twice daily) for
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600 mg/day
100 mg/day 0 mg/day Screening Titration
Fixed dose
Taper
Washout
Weeks –2
Semen analysis
0
2
Semen analysis
12
13
Semen analysis
26
Semen analysis
Figure 1. Trial design. All dosing was twice a day: 100 mg/day = 50 mg 9 2; 600 mg/day = 300 mg 9 2. If subjects could not tolerate 600 mg/day, they received 450 mg/day. If subjects could not tolerate 450 mg/day, they were discontinued from the study.
10 additional weeks. Subjects who could not tolerate 600 mg/day were reduced, at the discretion of the investigator, to 450 mg/day for the remainder of the study. Subjects who could not tolerate 450 mg/day were discontinued from the study. Two semen samples were collected (48 to 96 hours apart) at screening, baseline (Week 0), end of treatment (Week 12), and after the washout period (Week 26). All semen evaluations at participating sites were performed in a standardized manner by technicians who were trained and certified at a central facility to ensure minimal technical variation. Analysis Sets Two different analyses sets were utilized in this study: as per protocol (PP) and modified intent-to-treat (mITT) populations. The PP population included all randomized subjects who received ≥ 8 weeks of study treatment, had 2 sperm concentration measurements at Week 12 and/or Week 26, did not discontinue due to site violations, and did not have any major protocol violations. The mITT population included all randomized subjects who received ≥ 1 dose of study medication and were not discontinued for a major protocol violation at the site level. Timepoints Three different timepoints were analyzed in this study: End of Study, Week 26, and Week 12. They differed
with respect to how missing subject data were handled. For the End of Study analysis, Week 26 data were used. However, if a subject was missing Week 26 data, the subject’s Week 12 data were included in the analysis. For the Week 26 analysis, only Week 26 data were used. If Week 26 data were missing, that subject was excluded from the analysis. For the Week 12 analysis, only Week 12 data were used. If Week 12 data were missing, that subject was excluded from the analysis. In the PP population, sperm concentration was based on the average of 2 semen samples taken 48 to 96 hours apart. If 1 of the 2 samples was missing at a particular timepoint, then the subject was excluded from analysis at that particular timepoint. In the PP population, Weeks 12 and 26 were defined as 70 to 98 and 168 to 196 days from study Day 1, respectively. In the mITT population, only 1 of 2 semen samples was necessary for inclusion in an analysis at a particular timepoint. In the mITT population, Weeks 12 and 26 were defined as 2 to 133 and 134 to 252 days from study Day 1, respectively. Outcome Measures The primary outcome measure (and basis for samplesize determination) was the proportion of subjects with a ≥ 50% reduction in sperm concentration from baseline to End of Study. The threshold of ≥ 50% greater reduction was chosen to allow for normal variations in
Pregabalin’s Lack of Effect on Sperm Production 153
sperm concentration within and between individuals.6–9 Secondary outcome measures included the change in serum FSH, serum testosterone, and sperm motility at End of Study, Week 26, and Week 12. Sperm morphology and semen volume were assessed at baseline, Week 12, and Week 26. Statistical Analysis The primary analysis tested the hypothesis that pregabalin is noninferior (no worse than) to placebo with respect to the proportion of subjects with a ≥ 50% decrease in sperm concentration. This analysis was performed in the PP population using End of Study data. Noninferiority of pregabalin, compared with placebo, was declared if the upper bound of the 2-sided 95% confidence interval (CI) for the difference between the 2 treatment groups was less than the prespecified margin of 20%.10–13 It was assumed that the proportion of subjects with a 50% reduction in sperm concentration would be 6% for both groups. Therefore, a sample size of 65 subjects per treatment group would provide > 90% power to show noninferiority of pregabalin to placebo. In order to account for subject discontinuations and protocol violations, 110 and 112 subjects were randomized to receive placebo and pregabalin, respectively. To support the primary analysis described above (PP population at End of Study), secondary analyses of the proportion of subjects with ≥ 50% reduction in sperm concentration were conducted at End of Study, Week 26, and Week 12 in the mITT population. Least squares mean changes in serum hormones (FSH and testosterone) and sperm motility at End of Study, Week 26, and Week 12 in the mITT population were analyzed using analysis of covariance (ANCOVA) with treatment and center as factors and baseline values as covariate in the model. All tests were performed at the 2-sided 5% significance level (P = 0.05). Mean changes in sperm morphology and semen volume at Weeks 12 and 26 were summarized descriptively in the mITT population, and no inferential testing was performed. Safety Measures The safety profile of pregabalin was assessed based on observed and reported adverse events (AEs), which were evaluated by the investigator for severity and relationship to study treatment. Additional safety
measurements included physical examinations and clinical laboratory tests. All subjects who received ≥ 1 dose of study treatment were in the safety analysis.
RESULTS A total of 222 subjects were randomized, 109 received placebo and 111 received pregabalin (Figure 2). Subject demographics were similar between treatment groups (Table 1). Median treatment duration was 92 and 90 days in the placebo and pregabalin groups, respectively. More than 75% of subjects in the pregabalin group received treatment for 70 to 98 days. A majority of pregabalin-treated subjects received a final dose of 600 mg/day (n = 100, 90%). The most frequently reported concomitant drug treatments were multivitamins (placebo: n = 6; pregabalin: n = 6) and ibuprofen (placebo: n = 5; pregabalin: n = 6). The proportion of subjects in the PP population who experienced a ≥ 50% reduction in sperm concentration at End of Study was 3.2% (n = 2) in the placebo group and 9.2% (n = 6) in the pregabalin group (Table 2). The upper bound of the 95% CI for the treatment difference between pregabalin and placebo was 14.30%, which was less than the prespecified noninferiority margin of 20%. Thus, pregabalin was not inferior to placebo with respect to the proportion of subjects who experienced a ≥ 50% reduction in sperm concentration at End of Study (Figure 3). This finding is supported by secondary analyses in the mITT population at End of Study (upper bound of 95% CI = 10.50%), Week 26 (upper bound = 12.33%), and Week 12 (upper bound = 6.87%; Table 2 and Figure 3). Pregabalin treatment increased FSH levels, compared with baseline, at End of Study (+ 0.39 IU/L), Week 26 (+ 0.10 IU/L), and Week 12 (+ 0.29 IU/L). However, these changes were small and not significantly different from placebo (Table 3). Likewise, pregabalin-mediated changes in testosterone levels at End of Study (+ 1.17 ng/dL), Week 26 (+ 2.28 ng/dL), and Week 12 ( 12.85 ng/dL) were minor and not significantly different from placebo (Table 3). Sperm motility was also decreased in the pregabalin group compared to baseline but, again, these changes were small and not significantly different from placebo; the percentage of subjects with grade a + b motility decreased by 3.98% at End of Study, 3.82% at Week 26, and 3.73% at Week 12 (Table 3). Although no inferential statistical testing was performed, there appeared to be no difference between
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Screened (n=903)
Randomized to placebo (n=110)
Randomized to pregabalin (n=112)
Treated (n=109)
Treated (n=111)
Discontinued: 39 (35.8%) Lost to follow-up: 10 (9.2%) No longer willing to participate: 9 (8.3%) Protocol violation: 9 (8.3%) Adverse event: 0 Study terminated by sponsor: 3 (2.8%) Other: 8 (7.3%)
Discontinued: 34 (30.6%) Lost to follow-up: 7 (6.3%) No longer willing to participate: 2 (1.8%) Protocol violation: 9 (8.1%) Adverse event: 5 (4.5%) Study terminated by sponsor: 3 (2.7%) Other: 8 (7.2%)
Ongoing: 2 (1.8%)a
Ongoing: 0
Completed: 70/109 64.2%
Completed: 75/111 67.6%
Semen analysis PP: 62 (56.9%) mITT: 88 (80.7%)
Semen analysis PP: 65 (58.6%) mITT: 90 (81.1%)
Safety analysis: 109 (100%)
Safety analysis: 111 (100%)
Figure 2. Subject disposition. aAt time of database release, 2 subjects in the pregabalin treatment group were classified as “ongoing” due to delayed collection of subject summary page. Both subjects completed treatment. mITT, modified intention to treat; PP, per protocol.
Table 1. Subject Demographics Number (%) of Subjects
Age, years Mean (SD) Range Race, % White Black Asian Other Weight, kg Mean (SD) Range Height, cm Mean (SD) Range SD, standard deviation.
Placebo (n = 109)
Pregabalin (n = 111)
32.1 (9.4) 19 to 55
31.1 (9.0) 18 to 52
84 (77.1) 14 (12.8) 5 (4.6) 6 (5.5)
85 (76.6) 14 (12.6) 5 (4.5) 7 (6.3)
89.3 (20.7) 44.9 to 195.5
89.2 (18.8) 52.6 to 158.7
178.5 (8.2) 147.0 to 203.0
178.7 (7.5) 160.0 to 206.0
pregabalin and placebo groups with respect to sperm morphology or semen volume at Weeks 12 or 26 (Table 4). AEs were reported more frequently in the pregabalin group compared with placebo (Table 5). A majority of all AEs were mild (78.9%), and there were no severe AEs associated with pregabalin treatment. There were no serious AEs in either treatment group. Few subjects (< 5%) discontinued due to an AE or had a temporary discontinuation/dose-reduction due to an AE (< 9%). The most common treatment-related AEs in the pregabalin group were dizziness, somnolence, euphoric mood, fatigue, and paresthesia. There were no clinically significant changes related to laboratory tests, vital signs, or physical examinations.
Pregabalin’s Lack of Effect on Sperm Production 155
Table 2. Percentage of Subjects with ≥ 50% Reduction in Mean Sperm Concentration from Baseline Placebo PP end of study, N Subjects with ≥ 50% mITT end of study, N Subjects with ≥ 50% mITT Week 26, N Subjects with ≥ 50% mITT Week 12, N Subjects with ≥ 50%
decrease, n (%) decrease, n (%) decrease, n (%) decrease, n (%)
62 2 72 5 60 3 72 7
(3.2) (6.9) (5.0) (9.7)
Pregabalin 65 6 79 7 69 6 79 6
(9.2) (8.9) (8.7) (7.6)
PP, per protocol; mITT, modified intention to treat.
Pregabalin non-inferior to placebo
Table 3. Mean Change in FSH, Testosterone, and Sperm Motility from Baseline*
Pregabalin inferior to placebo
miTT Week 12 miTT Week 26 miTT End of Study PP End of Study
–20 –10 0 10 20 30 Percent difference between pregabalin and placebo
Figure 3. Treatment difference between pregabalin and placebo. Data shown are mean 95% confidence interval. The prespecified noninferiority margin of 20% is shown as a vertical dashed line. mITT, modified intention to treat; PP, per protocol.
DISCUSSION This phase 4, double-blind, randomized, placebo-controlled, multicenter study demonstrates that treatment with 600 mg/day pregabalin for 12 weeks has no significant effects on sperm production in healthy men aged 18 to 55 years. Pregabalin was not inferior to placebo with respect to the proportion of subjects with ≥ 50% reduction in sperm concentration at End of Study. The benchmark of ≥ 50% reduction in sperm concentration has been used in previous noninferiority studies10,12,13 and was chosen to account for normal physiological variations in sperm production.6–9 The primary analysis of sperm concentration was based on End of Study data. This means that, ideally, semen samples were collected and analyzed after subjects had undergone 12 weeks of pregabalin treatment (1 full spermatogenesis cycle) and 13 weeks of taper/washout (another full spermatogenesis cycle).14 This endpoint was based on discussions with the US
Placebo FSH, IU/L End of study N LS mean LS mean difference† 95% CI P value‡ Week 26 N LS mean LS mean difference† 95% CI P value‡ Week 12 N LS mean LS mean difference† 95% CI P value‡ Testosterone, ng/dL End of study N LS mean LS mean difference† 95% CI P value‡ Week 26 N LS mean LS mean difference† 95% CI P value‡ Week 12 N LS mean LS mean difference† 95% CI P value‡ Sperm motility,%§ End of study N LS mean LS mean difference‡ 95% CI P value‡ Week 26 N LS mean LS mean difference† 95% CI P value‡ Week 12 N LS mean LS mean difference† 95% CI P value‡
Pregabalin
72 0.51 – – –
79 0.39 0.12 ( 0.39, 0.14) 0.35
60 0.23 – – –
69 0.1 0.13 ( 0.42, 0.16) 0.37
72 0.5 – – –
79 0.29 0.2 ( 0.46, 0.05) 0.12
72 23.48 – – –
79 1.17 24.65 ( 21.00, 70.30) 0.29
60 30.65 – – –
69 2.28 32.93 ( 14.29, 80.16) 0.17
72 6.72 – – –
79 12.85 6.12 ( 52.80, 40.56) 0.8
73 2.9 – – –
79 3.98 1.08 ( 3.65, 1.49) 0.41
60 3.67 – – –
69 3.82 0.15 ( 2.65, 2.35) 0.91
73 2.87 – – –
79 3.73 0.86 ( 3.21, 1.48) 0.47
*Based on the modified intention-to-treat population. † Pregabalin – placebo. ‡ Versus placebo. § Grade a + b. Higher values indicate greater progressive motility. FSH, follicle-stimulating hormone; LS, least squares; CI, confidence interval.
Food and Drug Administration and with the rationale that the full effect of pregabalin exposure would be evident in the spermatogenesis cycle (12 to 13 weeks)
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Table 4. Summary of Semen Volume and Sperm Morphology*
Semen volume, mL Baseline N Mean (SD) Week 12 N Mean (SD) Week 26 N Mean (SD) Normal sperm morphology†,% Baseline N Mean (SD) Week 12 N Mean (SD) Week 26 N Mean (SD)
Placebo
Pregabalin
88 2.56 (1.02)
90 2.98 (1.14)
73 2.52 (1.08)
79 3.09 (1.55)
60 2.45 (0.98)
69 2.89 (1.13)
88 44.39 (7.39)
90 45.34 (6.33)
72 44.58 (6.32)
79 44.08 (6.30)
60 44.48 (7.53)
69 44.79 (6.76)
*Based on the modified intention-to-treat population. †Refers to the percentage of sperm with normal head. SD, standard deviation.
Table 5. Summary of Adverse Events, Number (%) of Subjects All Causalities
Number of AEs Subjects with an AE Subjects with a SAE Subjects with a severe AE Subjects discontinuations due to an AE Subjects with dose reductions or temporary discontinuation due to an AE Common AEs* Dizziness Somnolence Euphoric mood Fatigue Headache Muscle strain Paresthesia Nausea
Treatment-related
Placebo (n = 109)
Pregabalin (n = 111)
Placebo (n = 109)
Pregabalin (n = 111)
70 45 (41.3)
148 61 (55.0)
31 21 (19.3)
100 48 (43.2)
0
0
0
0
2 (1.8)
1 (0.9)
1 (0.9)
0
0
5 (4.5)
0
5 (4.5)
0
9 (8.1)
0
8 (7.2)
1 5 1 1 5 1 1 4
(0.9) (4.6) (0.9) (0.9) (4.6) (0.9) (0.9) (3.7)
21 11 6 5 4 4 4 2
(18.9) (9.9) (5.4) (4.5) (3.6) (3.6) (3.6) (1.8)
1 5 1 1 4 0 0 4
(0.9) (4.6) (0.9) (0.9) (3.7)
(3.7)
20 11 6 5 3 0 4 1
(18.0) (9.9) (5.4) (4.5) (2.7) (3.6) (0.9)
*Occurring in ≥ 3% of subjects. AE, adverse event; SAE, serious adverse event.
after discontinuation of treatment. To support the primary analysis, the proportion of subjects with ≥ 50% reduction in sperm concentration was also
analyzed in the mITT at End of Study, Week 26, and Week 12. In all cases, pregabalin was not inferior to placebo. These data demonstrate that pregabalin does not affect the spermatogenesis cycle that occurs concurrent to treatment (Week 12 data), nor the spermatogenesis that follows discontinuation of treatment (Week 26 and End of Study data). A total of 8 subjects (pregabalin = 6, placebo = 2) had a ≥ 50% reduction in sperm concentration at Week 26. However, for 7 of these subjects, changes in sperm concentration reverted to less than 50% after a 3-month (1 spermatogenesis cycle) follow-up period. Men who have low sperm concentration often also have abnormal sperm motility and morphology.15,16 In the current study, pregabalin treatment was not associated with any significant effect on progressive motility or total sperm motility compared with placebo. This was evident immediately following cessation of treatment at Week 12 and following the washout period at Week 26. Although no inferential statistical testing was performed, sperm morphology and semen volume were also numerically similar between pregabalin and placebo groups following both the treatment (Week 12) and washout (Week 26) periods. Additionally, pregabalin treatment was not associated with any significant change in the serum concentration of the reproductive hormones, FSH or testosterone. These findings are broadly consistent with a previous randomized, controlled trial of the effects of pregabalin on reproductive parameters in healthy male volunteers (unpublished data; Pfizer protocol 1008-072). In this previous study, which was powered to examine pregabalin’s effect on sperm motility, 30 subjects received 600 mg/day pregabalin for 3 months. The difference between placebo- and pregabalin-treated subjects, with respect to the percentage of sperm with normal motility, was < 4%; the percentage of motile sperm did not change more than 2% from baseline in either treatment group. The previous trial also examined sperm morphology, semen volume, and sperm concentration as secondary endpoints and, as in the current trial, no significant differences between placebo and pregabalin treatment were reported. The dose of 600 mg/day was chosen in the current trial and in the previous trial, because it is the maximum recommended daily dose of pregabalin.1 This dose of pregabalin was well-tolerated in healthy subjects in this study. Nearly 80% of all AEs were mild in severity and only < 5% of subjects in the pregabalin group discontinued treatment due to an AE. Furthermore, the AE
Pregabalin’s Lack of Effect on Sperm Production 157
profile in these subjects was similar to the known profile for pregabalin. A potential limitation of multicenter sperm studies could be variability in semen analysis. However, such variability was taken into account during design of the study and was closely controlled by following standardized techniques for the evaluation of semen volume, sperm concentration, and sperm motility. These evaluations were performed by a trained and certified laboratory technician at each participating site. In addition, sperm morphology slides were prepared by trained site technicians according to a standardized protocol, and the evaluations were conducted at a central facility by a central reader, thus ensuring minimal technical variation. Another potential limitation is the inability to extrapolate our findings to other populations, such as healthy men < 18 or > 55 years of age or men with abnormal semen parameters. Finally, subjects in the current study were treated with pregabalin for 12 weeks (only 1 spermatogenesis cycle), and thus, we cannot extrapolate our findings beyond this treatment duration. Overall, our findings demonstrate that treatment with 600 mg/day pregabalin for 12 weeks does not adversely affect spermatogenesis, as well as serum levels of FSH and testosterone in healthy males.
DISCLOSURES The preliminary study data was presented by Dr. Sikka at the 10th International Congress of Andrology in Melbourne, Australia, 23 to 26 February, 2013 (Andrology, 2013, suppl 1, 99). S. Sikka received standardized semen analysis training and centralized morphology slide reading contracts from Pfizer for this study. E. Dula has served as a clinical research investigator for Repros Therapeutics, Allergan, Nymox Pharmaceutical, Serenity Pharmaceuticals, Boehringer Ingelheim, Pfizer and Endo Pharmaceuticals. W. Hellstrom serves or has served as a consultant/advisor to American Medical Systems, Andromedical, Auxilium, Allergan, Coloplast, Cook, Endo, Johnson & Johnson, Lilly U.S.A., Slate Pharmaceutical, and Vivus; has been a meeting participant or lecturer on behalf of Auxilium, Cook, Endo, Johnson & Johnson, Lilly U.S.A., Slate Pharmaceutical, and Vivus; has acted as an investigator in a study or trial for Auxilium, Allergan, Coloplast, Endo, Johnson & Johnson, Slate Pharmaceutical, and Vivus; and serves as a board member, officer, or trustee for Theralogix and the National
Institutes of Health. C. Chen, M. Almas, and L. Knapp are full-time employees of, and hold stock in, Pfizer Inc. This study was sponsored by Pfizer Inc. Medical writing support was provided by Matt Soulsby, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc.
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