Abstract
Objective:
To determine men’s satisfaction with and the potential acceptability of 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC).
Study design:
We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11β-MNTDC for male contraception.
Results:
Of 42 trial participants, 40 (30 11β-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11β-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel.
Conclusion:
A majority of participants in this short-term trial of daily oral 11β-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects.
Implications:
Oral 11β-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11β-MNTDC.
Keywords: Male contraception, Male birth control, Male birth control pill, Men’s family planning, Men’s sexual and reproductive health, Contraceptive development, Suppression of spermatogenesis, Hormonal contraception
1. Introduction
Currently available methods of reversible contraception are primarily developed for female users. However, among couples for whom female contraceptives are contraindicated, not used or used inconsistently, there is a need for reversible male contraceptive options. A reversible hormonal male contraceptive (HMC) could supplement contraceptive coverage among these couples [1], and reduce the global burden of unplanned pregnancy [2]. Additionally, reversible male contraceptives may be appealing to men who wish to control their fertility [3], and could improve men’s engagement in reproductive responsibility and decisions about family planning [4]. Several global surveys suggest that men are interested in the ideas of HMCs—in one survey of 1829 men from 4 countries across 3 continents, a high proportion of respondents (44–83% depending on location) reported willingness to use a theoretical HMC pill [5]. In another global survey of more than 9000 men from 9 countries across 4 continents, just over half (55%) reported acceptability of a novel HMC [6]. In addition, surveys of women indicate that they would trust their male partners to use HMC [7], suggesting a societal shift in attitudes toward greater male responsibility in family planning and a willingness to consider novel reversible male contraceptives.
The mechanism of action for HMCs is well understood—exogenous androgens act on the hypothalamic-pituitary axis to suppress testicular testosterone production, while maintaining serum androgens to prevent hypogonadism. Androgen and progestin combination regimens result in more rapid, complete and consistent suppression of circulating gonadotropin concentrations and spermatogenesis, while also decreasing the androgen dosage required for contraception [8]. Several phase II and phase III male contraceptive efficacy trials have demonstrated effective prevention of pregnancy with HMC injections, with failure rates of 0.8 to 2.3 pregnancies per 100 couple-years [9–14], comparable to failure rates of hormonal female methods of 0.3 to 7 pregnancies/100 woman-years [15]. Evidence for the acceptability of experimental HMC formulations exists in prior surveys from trials of HMC transdermal gels and injections [16–19]. Population surveys indicate men’s preference for an oral HMC pill over alternative formulations [5,6]; these surveys support the development of an oral HMC pill prototype. The poor bioavailability or frequent dosing requirements of available oral androgens, however [20,21], might factor into why few oral HMC candidates are in clinical trials.
Given the limitations of oral HMC development, only 2 studies report on the acceptability of investigational oral HMCs in the clinical trial setting. One survey study examined the acceptability of an oral regimen containing methyltestosterone and oral medroxyprogesterone [22]. Unfortunately, methyltestosterone produced an unacceptable number of adverse events, including hepatotoxicity. Another recent study reported on the acceptability of a 28-day oral regimen of dimethandrolone undecanoate (DMAU), a novel orally bioavailable androgen with progestational activity. More than three-quarters of respondents from this placebo-controlled trial expressed satisfaction with the method and would recommend it to others [23].
In a phase 1b clinical trial of oral 11β-methyl-19-nortestosterone (11β-MNTDC), a novel selective androgen receptor modulator with both androgenic and progestational activity, we randomized young, healthy men to receive placebo, 200 mg, or 400 mg doses of 11β-MNTDC for 28 consecutive days [24]. As the absorption of 11β-MNTDC is markedly improved when administered with a high fat meal [25], we asked participants to increase their fat intake at breakfast throughout the trial. We present the results from acceptability assessments of these trial participants, examining their willingness to use and adhere to an oral HMC pill regimen in the face of required changes in their behavioral routines, as well as participants’ assessments of potential side effects related to the drug.
2. Materials and methods
2.1. Study design
The design of this randomized, double-blind, placebo-controlled phase Ib study has been previously described [24]. In brief, we recruited healthy men, ages 18 to 50 years, at the Lundquist Institute in Los Angeles, California and the University of Washington in Seattle, Washington. We randomly assigned participants in a 3:1 ratio to receive active drug or placebo, with a target of 15 unique participants in each of the 200 mg and 400 mg groups, and an additional 5 placebo recipients per dosing group. Participants were recruited in a dose-escalation manner, with a safety assessment midway through a dosage group before finishing the dose group and proceeding to the next higher dosage. We instructed participants to take capsules every morning (2 pills in the 200 mg group; 4 pills in the 400 mg group) and within 30 minutes of consuming a meal containing 25 to 30 g of fat, given the improved absorption of 11β-MNTDC when administered with a high-fat meal [25]. The participants used the drug or placebo for 28 consecutive days. We assessed drug safety and tolerability twice per week and assessed pharmacokinetics and pharmacodynamics with serial blood sampling on days 1 and 28 for all participants. For the acceptability assessment, participants completed a baseline survey on their experience with contraceptives, followed by an end-of-treatment survey assessing their trial experience, satisfaction with, and willingness to use daily oral 11β-MNTDC if made available as hormonal male contraception (see Supplemental Survey).
All participants provided written informed consent for this trial, which was registered on ClinicalTrials.gov (NCT03298373) and approved by the local institutional review board (IRB) and the IRB contracted by the National Institute of Child Health and Human Development Contraceptive Clinical Trial Network Data and Statistical Coordinating Center (Advarra, Columbia, MD). We informed participants that they could not rely on the study drug for contraception. All sexually active participants confirmed their use of an approved, effective form of contraception throughout the study.
2.2. Survey instrument
We adapted surveys used in this trial from published HMC acceptability studies [16–19]. We also added several novel questions to the current study survey, aimed at providing practical insights about men’s projected HMC utilization, specifically regarding their ability to adhere to a daily oral regimen and their willingness to pay for a hormonal contraceptive method.
At the baseline visit, we asked participants about their perceptions of contraceptive method availability and their role in contraceptive decision-making (male partner primary, female partner primary, or shared). We also asked participants via 4-point Likert scale to rate their anticipated likelihood of missing a dose of the study drug (never, unlikely, somewhat likely, very likely) and their concerns about its safety (not at all concerned, somewhat unconcerned, somewhat concerned, very concerned).
Upon completion of the treatment phase, we assessed the participants’ experience of using the study drug by asking them to rate their agreement via 4-point Likert scale (strongly disagree, disagree, agree, strongly agree) with statements about perceived ease of using the drug, bothersome side effects, and their worries attributed to the study drug (e.g., unknown side effects and safety profile). We also inquired about perceptions of drug acceptability, including satisfaction with the study drug, willingness to use at no cost, willingness to use if having to pay, and willingness to recommend the study drug to others for contraception using the same scale. We asked participants to project how much they would pay for the study drug in an open-ended item, how long they would use the method, their preferences for the pill versus another route of administration, and where they would go to obtain an HMC. The survey concluded with open-ended questions about the advantages and disadvantages of the study drug and its administration, as well as the participants’ perceived benefits and detriments of the study drug (see Supplemental Survey).
2.3. Statistical analysis
The sample size in this phase Ib study provided at least 80% statistical power to detect serious adverse events occurring in 20% of men [24]. The fixed sample size (n = 40 participants completing the treatment phase) allowed for a descriptive analysis of perceived drug acceptability, according to receipt of active drug versus placebo. We combined data from both the 200 mg and 400 mg dose recipients in our comparison of outcomes with drug versus placebo due to the analytical limitations of small numbers. To identify any differences between the active drug versus placebo groups, we collapsed responses to the drug acceptability and user experience items—“strongly disagree” and “disagree” into “disagree,” and “strongly agree” and “agree” into “agree.” We then performed bivariate analyses to examine for any differences in participant characteristics, trial experiences, and projected acceptability, by receipt of active drug versus placebo using χ2 or Fisher’s exact tests where appropriate. We similarly explored factors associated with satisfaction with the study drug regimen. Given the exploratory nature of this analysis, we did not correct for multiple comparisons. Participant projections of cost, preferred routes of administration, and where they would obtain their HMC are presented via simple descriptive statistics.
For open-ended responses to questions about projected benefits and problems of HMCs, as well as what the participants liked and did not like about the study drug, 2 members of the research team (B.T.N. and F.Y.) used inductive coding to identify salient, recurring themes. The researchers coded the responses independently and compared codes, revising them iteratively to reach consensus. We quantified the prevalence of themes among participants using simple descriptive statistics. Given that participants did not consistently distinguish between open-ended questions about perceived benefits versus reasons why they liked the pill, as well as questions about perceived problems versus reasons why they did not like the pill, we collapsed the responses into positive and negative attributes, respectively [see Supplemental Survey]. We additionally examined an open-ended item on reasons why individuals considered stopping the pill, combining all codes referencing negative side effects experienced by the participant to examine for any association between such experiences and study drug acceptability via bivariate analysis using Fisher’s exact tests.
3. Results
3.1. Baseline data
Of the 42 men enrolled in the study, 40 men completed the treatment (10 on placebo, 15 on 200 mg, 15 on 400 mg). All 40 men who completed the treatment, also completed the baseline and end-of-treatment acceptability surveys. There were no baseline differences between the placebo and active treatment groups (Table 1). One participant in the placebo group and 1 participant in the 400 mg group discontinued the trial early. The participants comprised a racially diverse population (33% Hispanic or Latino, 24% non-Hispanic Asian, 21% non-Hispanic White, 17% non-Hispanic Black) with a median age of 28.5 (range: 19–47 years). The majority reported graduating with at least a 2-year college degree (52%). Few participants reported being married (12%). Of note, 29% reported not having had vaginal intercourse in the month prior to trial enrollment; half reported having vaginal intercourse at least once per week (21%: 1×/week; 29% >1×/week). Nearly one-third of participants (31%) primarily relied upon female-controlled methods of contraception at baseline.
Table 1.
Baseline oral hormonal male contraceptive trial participant demographics and reproductive characteristics, by receipt of placebo versus active drug (11β-MNTDC); n=42 participants, United States, 2017
| Participant Characteristics | Placebo n=11 (%) |
Drug n=31 (%) |
All n=42 (%) |
p-value (Placebo vs Drug) |
|
|---|---|---|---|---|---|
|
Age at consent
(years) |
Mean | 27.1 | 30.7 | 29.8 | N/A |
| SD | 6.8 | 7.6 | 7.5 | ||
| Median | 25 | 31 | 28.5 | ||
| Min, Max | 20, 41 | 19, 47 | 19, 47 | ||
| Age (years) | 18–20 | 1 (9.1) | 1 (3.2) | 2 (4.8) | 0.33 |
| 21–30 | 7 (63.6) | 14 (45.2) | 21 (50.0) | ||
| 31–40 | 2 (18.2) | 12 (38.7) | 14 (33.3) | ||
| 41–50 | 1 (9.1) | 4 (12.9) | 5 (11.9) | ||
| Race/Ethnicity | Non-Hispanic Asian | 2 (18.2) | 8 (25.8) | 10 (23.8) | 0.43 |
| Non-Hispanic Black | 1 (9.1) | 6 (19.4) | 7 (16.7) | ||
| Hispanic or Latino | 3 (27.3) | 11 (35.5) | 14 (33.3) | ||
| Non-Hispanic White | 5 (45.5) | 4 (12.9) | 9 (21.4) | ||
| Mixed or Other | 0 (0.0) | 2 (6.4) | 2 (4.8) | ||
| Education level | High school graduate or less | 0 (0.0) | 4 (12.9) | 4 (9.5) | 0.20 |
| Some college, no degree | 3 (27.3) | 13 (41.9) | 16 (38.1) | ||
| College graduate (2-yr or 4-yr) | 7 (63.6) | 8 (25.8) | 15 (35.7) | ||
| Master’s or Doctorate | 1 (9.1) | 6 (19.4) | 7 (16.7) | ||
| Marital status | Married | 0 (0.0) | 5 (16.1) | 5 (11.9) | 0.30 |
| Not Married | 11 (100.0) | 26 (83.9) | 37 (88.1) | ||
| Frequency of vaginal intercourse in the month prior to trial enrollment | None | 3 (27.3) | 9 (29.0) | 12 (28.6) | 0.06 |
| <1x/week | 2 (18.2) | 3 (9.7) | 5 (11.9) | ||
| 1x/week | 0 (0.0) | 9 (29.0) | 9 (21.4) | ||
| >1x/week | 3 (27.3) | 9 (29.0) | 12 (28.6) | ||
| No female partner | 3 (27.3) | 1 (3.2) | 4 (9.5) | ||
| Contraceptive method used prior to trial enrollment | Condoms | 0 (0.0) | 5 (16.7) | 5 (12.5) | 0.20 |
| Withdrawal | 2 (20.0) | 4 (13.3) | 6 (15.0) | ||
| Vasectomy | 0 (0.0) | 1 (3.3) | 1 (2.5) | ||
| Female-controlled method | 3 (27.3) | 10 (32.3) | 13 (31.0) | ||
| No method | 5 (50.0) | 10 (33.3) | 15 (37.5) | ||
With respect to baseline participant attitudes on contraception (Table 2), 83.3% believed that they had too few contraceptive options available. Nevertheless, most participants (79%) rated contraceptive decision-making as easy and for those in an active sexual relationship, more than half of those with a female partner shared contraceptive decision-making with their partner (58%) and reported their partner’s opinion as at least somewhat important (57%). With respect to attitudes about taking an oral study drug, 81% of participants predicted that they would never or be very unlikely to miss a dose during the trial; only 19% of participants reported being at least somewhat concerned about the safety of the study drug at the time of enrollment. These characteristics also did not differ significantly by randomization to placebo versus active drug.
Table 2.
Baseline oral hormonal male contraceptive trial participant contraceptive experience and perspectives, by receipt of placebo versus active drug (11β-MNTDC); n=42 participants, United States, 2017
| Participant Characteristics | Placebo n=11 (%) |
Drug n=31 (%) |
All n=42 (%) |
p-value (Placebo vs Drug) |
|
|---|---|---|---|---|---|
| Perception of number of contraceptives available | Too many | 0 (0.0) | 1 (3.2) | 1 (2.3) | 0.91 |
| About enough | 2 (18.2) | 4 (12.9) | 6 (14.3) | ||
| Too few | 5 (45.5) | 15 (48.4) | 20 (47.6) | ||
| Far too few | 4 (36.4) | 11 (35.5) | 15 (35.7) | ||
| Ease of contraception decision-making | Easy | 8 (72.7) | 25 (80.6) | 33 (78.6) | 0.82 |
| Difficult | 1 (9.1) | 3 (9.7) | 4 (9.5) | ||
| I am the only one who uses contraception | 2 (18.2) | 3 (9.7) | 5 (11.9) | ||
| Primary contraceptive decision-maker | Male partner | 2 (18.2) | 5 (16.1) | 7 (16.7) | 0.24 |
| Female partner | 0 (0.0) | 6 (19.4) | 6 (14.3) | ||
| Shared equally | 4 (36.4) | 14 (45) | 18 (42.9) | ||
| Not applicable | 5 (45.5) | 6 (19.4) | 11 (26.2) | ||
| Importance of female partner’s opinion | Not/slightly important | 3 (27.3) | 9 (29.0) | 12 (28.6) | 0.18 |
| Somewhat/very important | 2 (18.2) | 14 (45.2) | 16 (38.1) | ||
| Not applicable | 6 (54.6) | 8 (25.8) | 14 (33.3) | ||
| Concerns about missing a daily dose | Likely/somewhat likely | 4 (36.4) | 4 (12.9) | 8 (19.1) | 0.17 |
| Not at all likely/ somewhat unlikely |
7 (63.6) | 27 (87.1) | 34 (80.9) | ||
| Concerns about HMC safety | Very concerned/ somewhat concerned |
1 (9.1) | 7 (22.6) | 8 (19.1) | 0.66 |
| Somewhat unconcerned/ not at all unconcerned |
10 (90.9) | 24 (77.4) | 34 (80.9) | ||
3.2. End-of-study data: attitudes and acceptability
Upon study completion, most participants endorsed that they liked taking the pill (63%), and that it was easy to swallow (85%) and easy to remember (88%). Few participants reported taking the pill interfered with their daily routine (15%). Approximately one-third of participants reported having experienced bothersome side effects in the survey (37% 11β-MNTDC vs. 20% placebo, p = 0.45; Table 3). Three participants, all from the active group, reported that they often considered stopping the trial—one individual cited non-specific concerns about the risk of an experimental drug, one attributed wanting to stop due to hormonal side effects such as decreased libido and mood changes, and the other expressed being bothered both by hormonal side effects and having to eat a high fat breakfast each day as part of the trial.
Table 3:
Comparison of oral hormonal male contraceptive trial user-experience perceptions in end-of-treatment survey, by receipt of placebo versus active drug (11B-MNT); n=40 participants, United States, 2017
| Agreement with the questionnaire statement | Placebo n=10 (%) |
Drug n=30 (%) |
All, N=40 (%) |
p-value (Placebo vs Drug) |
|---|---|---|---|---|
| I LIKE TAKING the pill | 6 (60.0) | 19 (63.3) | 25 (62.5) | 0.85 |
| The pill was EASY TO SWALLOW. | 8 (80.0) | 26 (86.7) | 34 (85.0) | 0.63 |
| Taking the pill DAILY is EASY TO REMEMBER | 9 (90.0) | 26 (86.7) | 35 (87.5) | 0.78 |
| Taking the pill INTERFERED with my daily routine. | 1 (10.0) | 5 (16.7) | 6 (15.0) | 0.61 |
| I HAD MORE SEX while taking the pill | 2 (20.0) | 6 (20.0) | 8 (20.0) | 1.00 |
| SEX WAS BETTER while taking the pill | 2 (20.0) | 5 (17.2) | 7 (18.0) | 0.85 |
| I experienced SIDE EFFECTS that bothered me | 2 (20.0) | 11 (36.7) | 13 (32.5) | 0.45 |
| I worried about UNKNOWN side effects of the pill. | 5 (50.0) | 12 (40.0) | 17 (42.5) | 0.72 |
| I worried about the PILL NOT WORKING. | 3 (30.0) | 4 (13.3) | 7 (17.5) | 0.34 |
| I worried about the SAFETY of the pill to me. | 2 (20.0) | 9 (30.0) | 11 (27.5) | 0.70 |
With respect to acceptability (Table 4), the majority of participants reported satisfaction with the study drug (73% 11β-MNTDC vs. 70% placebo, p = 0.84), willingness to recommend the method to others (90% 11β-MNTDC vs. 100% placebo, p = 0.56), willingness to use the method as their primary method of contraception if available cost-free (87% 11β-MNTDC vs. 60% placebo, p = 0.09), and willingness to purchase the drug as their primary method of contraception (67% 11β-MNTDC vs. 50% placebo, p = 0.35). More than half of participants (50% 11β-MNTDC vs. 67% placebo, p = 0.51) affirmed that the method exceeded their initial expectations. Satisfaction with the study regimen did not correlate with any participant demographics (Table 5), except marginally for education whereby those with a master’s or doctoral degree more commonly reported being unsatisfied (71.4% vs. 28.6%, p = 0.04). With respect to contraceptive experience (Table 6), self-reported likelihood of missing a dose was the only participant characteristic linked to any reported dissatisfaction with the study drug (p = 0.03). Reported concerns about the safety of using HMCs did not correlate with reported satisfaction with the study regimen.
Table 4:
Comparison of oral hormonal male contraceptive trial drug acceptability and satisfaction in end-of-treatment survey, by receipt of placebo versus active drug (11B-MNT); n=40 participants, United States, 2017
| Measures of hormonal male contraceptive acceptability | Placebo n=10 (%) |
Drug n=30 (%) |
All, N=40 (%) |
p-value (Placebo vs Drug) |
|---|---|---|---|---|
| Overall, I was satisfied with this method of contraception | ||||
| Disagree | 3 (30.0) | 8 (26.7) | 11 (27.5) | 1.00 |
| Agree | 7 (70.0) | 22 (73.3) | 29 (72.5) | |
| If available today and provided at NO COST, I would use this method as my primary method | ||||
| Disagree | 4 (40.0) | 4 (13.3) | 8 (20.0) | 0.09 |
| Agree | 6 (60.0) | 26 (86.7) | 32 (80.0) | |
| If available today and I HAD TO PAY, I would use this method as my primary method | ||||
| Disagree | 5 (50.0) | 10 (33.3) | 15 (37.5) | 0.35 |
| Agree | 5 (50.0) | 20 (66.7) | 25 (62.5) | |
| I would recommend this method of contraception to others seeking contraception | ||||
| Disagree | 0 (0.0) | 3 (10.0) | 3 (7.5) | 0.56 |
| Agree | 10 (100.0) | 27 (90.0) | 37 (92.5) | |
| How did your experience with the use of this method compare with your expectations? | ||||
| Worse | 0 (0.0) | 5 (16.7) | 5 (12.8) | 0.51 |
| About the same | 3 (33.3) | 10 (33.3) | 13 (33.3) | |
| Better | 6 (66.7) | 15 (50.0) | 21 (53.9) | |
| Did you ever want to STOP TAKING THE PILL during the trial? How often did you think about it? | ||||
| Never or rarely (1x during the study) | 8 (80.0) | 22 (73.4) | 30 (75.0) | 0.78 |
| Sometimes (about 1x/week) | 2 (20.0) | 5 (16.6) | 7 (17.5) | |
| Very often or always (at least 1x/d) | 0 (0.0) | 3 (10.0) | 3 (7.5) | |
Table 5.
Satisfaction with oral hormonal male contraceptive trial drug by baseline participant characteristics; n=40 participants, United States, 2017
| Participant Characteristics | No, unsatisfied n=11 |
Yes, satisfied n=29 |
p-value (satisfied vs unsatisfied) |
|
|---|---|---|---|---|
| Study drug allocation (%) | Placebo | 3 (30.0) | 7 (70.0) | 1.00 |
| Drug | 8 (26.7) | 22 (73.3) | ||
| Age (%) | 18–20 | 0 (0.0) | 2 (100.0) | 0.40 |
| 21–30 | 8 (38.1) | 13 (61.9) | ||
| 31–40 | 3 (20.0) | 12 (80.0) | ||
| 41–50 | 0 (0.0) | 2 (100.0) | ||
| Race (%) | Non-Hispanic Asian | 1 (10.0) | 9 (90.0) | 0.12 |
| Non-Hispanic Black | 0 (0.0) | 6 (100.0) | ||
| Hispanic or Latino | 6 (42.9) | 8 (57.1) | ||
| Non-Hispanic White | 4 (50.0) | 4 (50.0) | ||
| Mixed or Other | 0 (0.0) | 2 (100.0) | ||
| Education level (%) | High school graduate or less | 1 (25.0) | 3 (75.0) | 0.04 |
| Some college, no degree | 3 (21.4) | 11 (78.6) | ||
| College graduate (either 2-yr or 4-yr) | 2 (13.3) | 13 (86.7) | ||
| Master’s or Doctorate | 5 (71.4) | 2 (28.6) | ||
| Marital status (%) | Married | 2 (40.0) | 3 (60.0) | 0.60 |
| Not Married | 9 (25.7) | 26 (74.3) | ||
| Frequency of vaginal intercourse (%) | None | 2 (16.7) | 10 (83.3) | 0.52 |
| <1x/week | 2 (66.7) | 1 (33.3) | ||
| 1x/week | 2 (22.2) | 7 (77.8) | ||
| >1x/week | 4 (33.3) | 8 (66.7) | ||
| No female partner | 1 (25.0) | 3 (75.0) | ||
Table 6.
Satisfaction with oral hormonal male contraceptive trial drug by contraceptive experience; n=40 participants, United States, 2017
| Participant Characteristics | No, unsatisfied n=11 (%) |
Yes, satisfied n=29 (%) |
p-value (satisfied vs unsatisfied) |
|
|---|---|---|---|---|
| Perception of number of contraceptives available | Too many | 1 (9.1) | 0 (0.0) | 0.24 |
| About enough | 0 (0.0) | 5 (17.2) | ||
| Too few | 5 (45.5) | 14 (48.3) | ||
| Far too few | 5 (45.5) | 10 (34.5) | ||
| Ease of contraception decision-making | Easy | 6 (54.6) | 25 (86.2) | 0.04 |
| Difficult | 3 (27.3) | 1 (3.5) | ||
| Don’t make decisions | 2 (18.8) | 3 (10.3) | ||
| Primary contraceptive decision-maker | Male partner | 1 (9.1) | 5 (17.2) | 0.61 |
| Female partner | 3 (27.3) | 3 (10.3) | ||
| Shared equally | 5 (45.5) | 12 (41.4) | ||
| Not applicable | 2 (18.2) | 9 (31.0) | ||
| Extent of discussion with female partner | Enough | 5 (45.5) | 16 (55.2) | 0.36 |
| Not enough | 4 (36.4) | 4 (13.8) | ||
| Not applicable | 2 (18.2) | 9 (31.0) | ||
| Importance of female partner’s opinion | Not/slightly important | 3 (27.3) | 7 (24.1) | 0.82 |
| Somewhat/very important | 5 (45.5) | 11 (37.9) | ||
| Not applicable | 3 (27.3) | 11 (37.9) | ||
| Concerns about missing a daily dose | Likely/somewhat likely | 5 (44.5) | 3 (10.3) | 0.03 |
| Never/unlikely | 6 (54.6) | 26 (89.7) | ||
| Concerns about HMC safety | Very/somewhat concerned | 2 (18.2) | 5 (17.2) | 1.00 |
| Somewhat/not at all concerned | 9 (81.8) | 24 (82.3) | ||
Participants’ projections for willingness to pay for a month’s supply ranged from $10 to $100 per month, with a median of $40. More than half of participants indicated that if using the study drug specifically for contraception that they would consider using condoms (70%) or an additional female-controlled method (64.8%) along with their HMC. Nearly 40% of participants expressed being unsure of how long they would consider using HMC pills; among the remainder, more than half (52%) projected that they would use the drug for more than 1 year. When given the option to rank experimental methods of HMC administration (see Supplemental Appendix 1), the majority of men preferred oral pills over 1-year and 3-month injectables (42.9% vs. 37.1% vs. 5.7%, respectively). Considering where men might obtain HMC pills in the future, our participants primarily preferred their primary care provider (39%) or community pharmacist (19%) over other options, such as urologists, family planning clinics, and reproductive health specialists.
3.3. End-of-study data: open-ended responses
With respect to participants’ open-ended responses to queries of their experience in the trial and attitudes about the study drug following trial completion (see Supplemental Appendix 2), benefits reported by participants included the following, in order of reporting frequency: convenience of a daily oral pill (14), potential for men’s involvement in pregnancy prevention (6), alleviation of women’s contraceptive burden (5), improvement in sexual function (3), opportunity to contribute to science (3), and alternative to condoms (2). Drawbacks included the following, in order of reporting frequency: drug administration with a high fat breakfast (7), worsening sexual function (6), mood changes (5), fatigue (5), weight gain (4), having to take too many pills each day in the trial (4), and concerns about adherence to a daily regimen (2). Bothersome side effects, as tabulated via open-ended responses, were more commonly reported among participants receiving active drug than placebo (22 active drug vs. 1 placebo).
4. Discussion
In this 28-day, placebo-controlled trial of a daily oral regimen of 11β-MNTDC, we noted consistently high ratings of drug acceptability, as defined by our participants’ ratings of satisfaction (72.5%), willingness to use the method as their primary method of contraception if available (62.5–80.0%), and willingness to recommend the method to others (92.5%). These findings are comparable to acceptability ratings for a similarly designed 28-day trial of oral DMAU [23]. More than half of participants also rated their trial experience as better than expected. Even when given the option of using a longer-acting annual or quarterly injectable, or a transdermal topical gel formulation, a plurality of participants (42%) from this trial preferred a daily oral pill. Of note, these participants had no experience with HMC injectable or topical formulations. Participants speculated that they would use the drug for a year if available, at a median cost of $40 per month. These acceptability and projected use data, along with preliminary data demonstrating effective suppression of serum gonadotropins and testosterone [24] as markers of spermatogenic suppression, indicate that a daily oral regimen of 11β-MNTDC should be studied further as a potential oral HMC.
Pervasive concerns about negative side effects related to the use of hormonal contraception highlight the importance of placebo-control trials, with attention to the participants’ attribution of adverse events to the study drug and how these experiences impact their perception of drug acceptability. As individuals may underreport negative side effects in active trial settings to avoid being discontinued from a compensated trial, our survey queried the participants’ experience of negative side effects in several ways: (1) a discrete, end-of-trial item about their experience of bothersome side effects—reported as present in one-third of participants, mainly in the active drug arm; (2) itemizing all problems perceived and disclosed by participants in an open-ended item, with nearly all problems being reported by active drug recipients; (3) characterizing reasons participants often considered stopping their participation during the trial, which noted the experience of possible hormonal side effects in 2 of 3 cases. Thus, while this study lacked the power to investigate differences in the incidence of individual side effects by receipt of active drug versus placebo, we acknowledge the plausibility of bothersome changes in sexual function, mood, weight gain, and fatigue among men using this 11β-MNTDC regimen. The experience of bothersome side effects and report of drug-related problems were not linked to overall ratings of satisfaction with the drug in this trial population.
There is no validated questionnaire for evaluating the acceptability of a male contraceptive. Previous male contraceptive acceptability surveys that queried adverse events via close-ended survey items precluded the possibility of capturing potential noncontraceptive benefits. Our survey improves upon this limitation via its inclusion of open-ended questions. With respect to problems experienced during the trial, nearly one-third of participants commonly commented on the inconveniences related to drug administration, which included the requirement that the study drug be administered daily, with breakfast containing 25 to 30 g fat, as well as the number of pills that needed to be ingested. We encountered similar problems in the 28-day trial of oral DMAU [23]. When analyzing food consumption logs from both groups of participants, we noted overall compliance. Of note, the requirement for participants to co-administer the drug with a morning meal containing 25 to 30 g of fat to ensure drug bioavailability might not be necessary as drug development continues [25]. Future formulations could be administered at a different meal (e.g., during lunch or dinner), which would more likely contain the necessary amount of fat compared to breakfast, a meal that is commonly light or skipped among US men. Further, once the optimal dose is determined, the number of capsules required may be reduced.
Strengths of this study include the availability of a placebo control group, baseline and end-of-treatment surveys, the recruitment of a diverse trial population, and the use of multiple modalities for assessing participants’ experience of side effects and acceptability. While the results of this study are promising, the short-treatment period precludes observations of potential adverse effects that might arise with longer term use of 11B-MNTDC and limits generalizations related to its ability to provide effective contraception, as well as inferences on long-term acceptability. Furthermore, the external validity of these assessments is subject to selection bias whereby the motivations and experiences of a group of healthy male volunteers might not be generalizable to a broader population of long-term users. For example, several participants reported being motivated by the opportunity to contribute to science and alleviate women’s reproductive burdens; they might not represent the broader population of men who might use an HMC pill. Further, participants provided contraceptive acceptability ratings with the assumption that the study drug could be used as an effective method of contraception. In a real-life setting where participants need to rely solely on the study drug to prevent pregnancy and may be less confident in its efficacy, attitudes about the HMC pill prototype might differ and future assessments of acceptability will need to incorporate the attitudes of female partners.
In conclusion, this placebo-controlled, early phase trial demonstrates that an oral HMC formulation containing 11B-MNTDC is acceptable. Participants gave high ratings of satisfaction with the drug, as well as endorsed willingness to pay for, personally use, and recommend the drug to others. These ratings did not differ significantly even among those reporting bothersome side effects and inconvenient drug administration parameters. The results from this trial should encourage further evaluation of 11B-MNTDC, as well as other novel androgenic steroids, for their potential as oral hormonal contraceptive pills.
Supplementary Material
Acknowledgments
We thank the study participants, study coordinators/nurses: Kathryn Torrez Duncan (University of Washington) and Xiaodan Han, Elizabeth Ruiz, and Lauryn Maes (The Lundquist Institute at Harbor UCLA Medical Center) for their work conducting this study, Abbey Townsend, Sarah Godfrey, Jerry Kinard, and Tricia Brady from Health Decisions for assistance with monitoring, Clint Dart from Health Decisions for data management, and Dr. Mark Payson from the National Institutes of Health for medical monitoring of the study.
Funding
The study was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Contraceptive Clinical Trials Network under contracts to the University of Washington (HHSN275201300025I; Task Order: HHSN27500003), The Lundquist Institute at Harbor-UCLA Medical Center (HHSN27520130024I; Task Order: HHSN27500004), and Health Decisions (HHSN2752012002). S.T.P. is also supported by the Robert McMillen Professorship in Lipid Research. A.T. was supported by National Institute of Diabetes, Digestive and Kidney Disease through the Diabetes, Obesity and Metabolism Training Program (T32 DK 007247). P.Y.L. is supported by NHLBI K24 HL138632. F.Y. is supported by NICHD F32 HD097932.
Footnotes
Conflict of Interest
B.T.N., M.F., A.T., F.F., B.D.A., J.E.L., S.T.P., and P.Y.L. have no relevant disclosures. F.Y.: Research support from Clarus Therapeutics. R.S.: Consultant for Clarus. Grants from Testosterone Replacement Therapy Manufacturer Consortium. J.K.A.: Consultant for Clarus Therapeutics. D.L.B.: PI on a Cooperative Research and Development Agreement with HRA Pharma. C.W.: Research support from Clarus Therapeutics.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.contraception.2021.06.009.
References
- 1.Dorman E, Perry B, Polis CB, Campo-Engelstein L, Shattuck D, Hamlin A, et al. Modeling the impact of novel male contraceptive methods on reductions in unintended pregnancies in Nigeria, South Africa, and the United States. Contraception 2018;97(1):62–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bearak J, Popinchalk A, Alkema L, Sedgh G. Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model. Lancet Glob Heal 2018;6(4):e380–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Dorman E, Bishai D. Demand for male contraception. In: Expert Rev Pharmacoecon Outcomes Res, 12; 2012. p. 605–13. [DOI] [PubMed] [Google Scholar]
- 4.United Nations. Programme of ActionInternational Conference on Population and Development (ICPD). Cairo, Egypt: UNFPA; 1994. [Google Scholar]
- 5.Martin CW, Anderson RA, Cheng L, Ho PC, van der Spuy Z, Smith KB, et al. Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Hum Reprod 2000;15(3):637–45. [DOI] [PubMed] [Google Scholar]
- 6.Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes toward male fertility control: results of a multinational survey on four continents. Hum Reprod 2005;20(2):549–56. [DOI] [PubMed] [Google Scholar]
- 7.Glasier AF, Anakwe R, Everington D, Martin CW, van der Spuy Z, Cheng L, et al. Would women trust their partners to use a male pill? Hum Reprod 2000;15(3):646–9. [DOI] [PubMed] [Google Scholar]
- 8.Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet 2006;367(9520):1412–20. [DOI] [PubMed] [Google Scholar]
- 9.World Health OrganizationContraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet (London, England) 1990;336(8721):955–9. [PubMed] [Google Scholar]
- 10.World Health Organization Task Force on Methods for the Regulation of Male FContraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 1996;65(4):821–9. [PubMed] [Google Scholar]
- 11.Gu Y-Q, Wang X-H, Xu D, Peng L, Cheng L-F, Huang M-K, et al. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab 2003;88(2):562–8. [DOI] [PubMed] [Google Scholar]
- 12.Gu Y, Liang X, Wu W, Liu M, Song S, Cheng L, et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab 2009;94(6):1910–15. [DOI] [PubMed] [Google Scholar]
- 13.Turner L, Conway AJ, Jimenez M, Liu PY, Forbes E, McLachlan RI, et al. Contraceptive efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab 2003;88(10):4659–67. [DOI] [PubMed] [Google Scholar]
- 14.Behre HM, Zitzmann M, Anderson RA, Handelsman DJ, Lestari SW, McLachlan RI, et al. Efficacy and safety of an injectable combination hormonal contraceptive for men. J Clin Endocrinol Metab 2016;101(12):4779–88 jc20162141. [DOI] [PubMed] [Google Scholar]
- 15.World Health Organization Family planning – a global handbook for providers, Geneva, Switzerland: WHO; 2018. https://www.who.int/reproductivehealth/publications/fp-global-handbook/en/. [Google Scholar]
- 16.Ringheim K Evidence for the acceptability of an injectable hormonal method for men. Fam Plann Perspect 1995;27(3):123–7. [PubMed] [Google Scholar]
- 17.Zhang L, Shah IH, Liu Y, Vogelsong KM, Zhang L. The acceptability of an injectable, once-a-month male contraceptive in China. Contraception 2006;73(5):548–53. [DOI] [PubMed] [Google Scholar]
- 18.Meriggiola MC, Cerpolini S, Bremner WJ, Mbizvo MT, Vogelsong KM, Martorana G, et al. Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men. Hum Reprod 2006;21(8):2033–40. [DOI] [PubMed] [Google Scholar]
- 19.Roth MY, Shih G, Ilani N, Wang C, Page ST, Bremner WJ, et al. Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial. Contraception 2014;90(4):407–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Täuber U, Schröder K, Düsterberg B, Matthes H. Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone. Eur J Drug Metab Pharmacokinet 1986;11(2):145–9. [DOI] [PubMed] [Google Scholar]
- 21.Wang C, Swerdloff RS. Androgen replacement therapy in hypogonadal men. In: Winters SJ, editor. Male Hypogonadism. Contemporary Endocrinology. Totowa, NJ: Humana Press; 2004. 10.1007/978-1-59259-727-7_18. [DOI] [Google Scholar]
- 22.Bain J, Rachlis V, Robert E, Khait Z. The combined use of oral medroxyprogesterone acetate and methyltestosterone in a male contraceptive trial programme. Contraception 1980;21(4):365–79. [DOI] [PubMed] [Google Scholar]
- 23.Nguyen BT, Farrant MT, Anawalt BD, Yuen F, Thirumalai A, Amory JK, et al. Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype. Contraception 2020;102(1):52–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yuen F, Thirumalai A, Pham C, Swerdloff RS, Anawalt BD, Liu PY, et al. Daily oral administration of the novel androgen 11β-MNTDC markedly suppresses serum gonadotropins in healthy men. J Clin Endocrinol Metab 2020;105(3):e835. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Wu S, Yuen F, Swerdloff RS, Pak Y, Thirumalai A, Liu PY, et al. Safety and pharmacokinetics of single-dose novel oral androgen 11 β-methyl-19-nortestosterone-17 β-dodecylcarbonate in men. J Clin Endocrinol Metab 2019;104(3):629–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.