Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype

Abstract

Objective

To determine men’s satisfaction with and acceptability of a once-daily, oral regimen of dimethandrolone undecanoate (DMAU) versus placebo when used for 28 days.

Study Design

After a Phase I double-blind, randomized, placebo-controlled, dose-escalating trial of oral DMAU for 28-days, 57 healthy male volunteers completed a survey assessing their experience and satisfaction with the regimen. In the trial, participants were randomized to receive up to 4 DMAU capsules daily versus placebo and instructed to ingest them within 30 minutes of consuming a high fat meal. Pharmacokinetic and pharmacodynamic profiles were performed, followed by a 6-week recovery phase. Participants were counseled that they could not rely on the drug for contraception.

Results

Fifty-seven participants were offered acceptability surveys (39 DMAU, 18 placebo). Most respondents, 80% (45/56), reported satisfaction with the method; 77% (44/57) would recommend it. 54% (31/57), reported that, if available, they would use the method as their primary contraceptive. More respondents reported satisfaction with active DMAU than placebo (87% vs. 67%; p=0.05). Most respondents, 91% (52/57), reported no difficulty with having to take up to 4 pills within 30 minutes of ingesting a high-fat meal.

Conclusion

Most participants reported that the study method, daily oral DMAU or placebo, was satisfactory and acceptable. Having to take the drug after a high-fat meal did not detract from acceptability.

Implications

Most participants in a 4-week trial of daily DMAU capsules would recommend and use the method. High satisfaction among DMAU and placebo groups affirms acceptability of a daily male contraceptive pill, warranting further study of oral DMAU.

1. Introduction

Contraceptive research and development efforts have focused on the female user, with under-exploration of the role of male partners and men’s desire to control their reproductive future and share in the responsibility for family planning. Developing new male contraceptive methods has potential to reduce unintended pregnancies [1] and increase meaningful participation of males in family planning and reproductive health.

The acceptability of potential novel hormonal male contraception (HMC) is based on safety, effectiveness, convenience, mode of delivery, reversibility, availability, and other factors. Development of novel HMC has been hindered by the pharmaceutical industry’s assessment that HMC would have low acceptability and low utility, subsequently leading to low profitability [2]. However, multiple population surveys and several surveys of HMC trial participants demonstrate a significant interest in and willingness to use HMCs [3–6] and confirm that women in stable relationships will trust male partners to use HMC correctly [7, 8].

Research and development on HMC began almost fifty years ago [9] with the administration of exogenous testosterone (T) alone or later in combination with a progestin [10]. The principal mechanism of action of HMC is the reversible suppression of the hypothalamic-pituitary-testicular axis and subsequent inhibition of spermatogenesis [2]. The tolerability, efficacy and acceptability of this mechanism has additionally been confirmed in an international, multi-site clinical trial using 8 weekly combination of testosterone plus progestin intramuscular (IM) injections [4]. Relative disadvantages include the need for frequent injections, visits to healthcare providers to administer the drug, and the discomfort associated with the IM route. Accordingly, men have reported greatest interest in pill-based HMC formulations [6]; however pill development has been hindered by the rapid first pass metabolism of testosterone by the liver [11, 12].

Recently, novel androgen esters with better oral bioavailability, such as dimethandrolone undecanoate (DMAU), have been recently developed for HMC. DMAU is hydrolyzed in vivo to dimethandrolone (DMA), which reversibly binds to both testosterone and progesterone receptors [13]. In animal studies, DMA produces favorable effects, similar to T, on body composition and bone mineral density [14].

We demonstrated in a randomized, double-blind, placebo-controlled, 28-day Phase 1 clinical trial of young healthy men that 200 and 400 mg of daily oral DMAU taken after a high-fat meal, rapidly and safely reduced serum gonadotropin concentrations to low levels in most subjects [15]. In order to assess the acceptability of the first phase of this novel potential oral HMC, we asked the participants to complete a survey to evaluate their experiences and attitudes related to the study drug. Surveys of participant satisfaction and method acceptability for promising oral MHC prototypes, like oral DMAU, have not yet been performed. We hypothesized that the majority of participants would report that daily oral capsule ingestion is acceptable, and that acceptability of active and placebo capsules would be similar.

2. Materials and Methods

2.1. Study Design

The study design for the Phase 1, 28-day randomized, double-blind, placebo-controlled, dose-escalating trial of DMAU has been described. To summarize, healthy young men were randomized to active drug versus placebo in five groups: 100, 200, or 400 mg DMAU in 70% castor oil/30% benzyl benzoate, or 200 or 400 mg DMAU powder in 1,2 or 4 capsules. Participants were instructed to take capsules within 30 minutes of consuming a meal containing 25–30g of fat. They also received dietary education and an information sheet with examples of high fat food as well as combinations of high fat food often encountered when dining out. During treatment, pharmacokinetic and pharmacodynamic profiles were performed, and participants completed written assessments of sexual function (7-day psychosexual diaries) [16], and mood (PHQ-9). Participants were followed during a recovery phase, with additional assessments obtained 6 weeks after the end of treatment during an end-of-study visit. Eighty-three participants completed the trial but only 82 participants met criteria for analysis of the primary and secondary outcomes of the principal study. Because the acceptability survey was designed and approved after the main study had started, it was offered to only 57 of the participants, all of whom agreed to participate without compensation. The majority of surveyed participants completed the questionnaire at the end of treatment (Day 28, 41/57); a smaller number completed it at the end of the recovery phase (Days 70–76, 11/57) with five receiving questionnaires at other times (1 during treatment and 4 during unscheduled visits). Response rate among the participants given the survey was 100%.

Participants were counseled before and during the study to use an approved form of contraception throughout the study period and instructed not to rely upon DMAU/placebo as a contraceptive. The protocol was approved by the institutional review board (IRB), contracted by the National Institute of Child Health and Human Development (NICHD) Contraceptive Clinical Trial Network (CCTN) Coordinating Center (Advarra, Columbia, MD 21046) and the local IRB from each participating site. All potential participants provided written informed consent prior to screening and any study procedures. DMAU was manufactured by Evestra Inc. (San Antonio, TX) or Ash Stevens Inc. (Detroit, MI). Capsules contained active DMAU in powder blend or active DMAU dissolved in castor oil/benzyl benzoate. Placebo capsules of powder or castor oil/benzyl benzoate and capsules containing active drug were manufactured, tested, and packaged under GMP conditions by Stanford Research International (Menlo Park, CA) or QS Pharma (Boothwyn, PA). This trial was registered at www.clinicaltrial.gov, NCT01382069 (27 June 2011).

2.2. Survey Instrument

There are no validated instruments to assess HMC acceptability. The survey used in this trial was adapted from surveys from published HMC acceptability studies [5, 7, 17–19] and included questions about the capsule, delivery requirements, current contraceptive use and method satisfaction (Survey in the Appendix).

The survey examined the user’s experience by asking for their agreement (Yes/No) to the following statements: “Instructions about how to take them were clear,” “The capsules are easy to swallow,” “The capsules are unpleasant in taste/texture,” “It was easy to take the pill at the same time each day,” and “The capsules leaked or broke.”

The survey gauged acceptability with several 5-point Likert-type items (Tables 2 & 3). The questions assessed the respondents’ experience with and acceptability of the capsule, the regimen (including timing after a high-fat meal), willingness to recommend the method, comparative satisfaction with previously used contraceptive methods, and the importance of concurrent prevention of sexually transmitted infections (STIs). Binary questions were answered “yes or “no”; other question responses were based on a 5-point Likert scale. Finally, participants were asked an open-ended question about their primary reason for participating in the trial.

Table 2.

Comparison of user-experience perceptions in males following 28 days of daily active drug (dimethandrolone undecanoate, DMAU) vs. placebo, in a phase 1 HMC trial.

Agreement with the survey statement	Drug n = 39 (%)	Placebo n = 18 (%)	All n = 57 (%)	p-value
Instructions about how to take them were clear	38 (97.4)	17 (94.4)	55 (96.5)	0.54
The capsules are easy to swallow	37 (94.9)	16 (88.9)	53 (93.0)	0.58
It was easy to take them at the same time each day	35 (89.7)	12 (66.7)	47 (82.5)	0.03
The capsules are unpleasant in taste or texture	3 (7.7)	2 (11.1)	5 (8.8)	0.65
Taking them on a full stomach was easy	37 (94.9)	16 (88.9)	53 (93.0)	0.58
The fat content needed in the meal before taking the capsules was difficult to adhere to	10 (25.6)	6 (33.3)	16 (28.1)	0.55
Needing to time the food with the capsules (<30 min) was problematic	2 (5.1)	3 (16.7)	5 (8.8)	0.31

Table 3.

Comparison of overall user-acceptability and satisfaction in male participants following 28 days of daily active drug, (dimethandrolone undecanoate, DMAU) vs. placebo, in a phase 1 hormonal male contraception (HMC) trial.

Acceptability measure†	Drug n = 38 (%)	Placebo n = 18 (%)	All n = 57 (%)	p-value
Overall, I was satisfied with this method of contraception
Strongly disagree	0 (0.0)	0 (0.0)	0 (0.0)
Disagree	2 (5.3)	0 (0.0)	2 (3.6)	0.03
Undecided	3 (7.9)	6 (33.3)	9 (16.1)
Agree	16 (42.1)	9 (50.0)	25 (44.6)
Strongly agree	17 (44.7)	3 (16.7)	20 (35.7)
If available today, I would use this method of contraception as my primary method
Strongly disagree	1 (2.6)	0 (0.0)	1 (1.8)
Disagree	1 (2.6)	1 (5.6)	2 (3.6)	0.10
Undecided	12 (31.6)	10 (55.6)	22 (39.3)
Agree	8 (21.1)	5 (27.8)	13 (23.2)
Strongly agree	16 (42.1)	2 (11.1)	18 (32.1)
I would recommend this method of contraception to others seeking contraception
Strongly disagree	0 (0.0)	0 (0.0)	0 (0.0)
Disagree	0 (0.0)	1 (5.6)	1 (1.8)	0.23
Undecided	7 (18.4)	5 (27.8)	12 (21.4)
Agree	15 (39.5)	8 (44.4)	23 (41.1)
Strongly agree	16 (42.1)	4 (22.2)	20 (35.7)
How did your experience with the use of this method of contraception compare with your expectations?
A lot worse	0 (0.0)	0 (0.0)	0 (0.0)
A little worse	4 (10.5)	0 (0.0)	4 (7.1)	0.19
About the same	15 (39.5)	12 (66.7)	27 (48.2)
A little better	13 (34.2)	3 (16.7)	16 (28.6)
A lot better	6 (15.8)	3 (16.7)	9 (16.1)
How would you compare this method to the contraceptive you or your partner used in the last month?
A lot worse	1 (3.0)	0 (0.0)	1 (2.0)
A little worse	1 (3.0)	1 (5.6)	2 (3.9)	0.98
About the same	13 (39.4)	7 (38.9)	20 (39.2)
A little better	9 (27.3)	6 (33.3)	15 (29.4)
A lot better	9 (27.3)	4 (22.2)	13 (25.5)

^†hormonal male contraception.

2.3. Statistical Analysis

We compared the acceptability of active drug versus placebo as the primary analysis of this acceptability sub-study. The main study objective was to examine optimal doses and optimal formulations of DMAU for gonadotropin suppression and drug safety and tolerability; the sub-study was not powered to examine differences in acceptability between the escalating doses or between the oil-based and powder-based DMAU formulations. For analysis, 5-point Likert items were collapsed into two categories to allow for bivariate analyses of acceptability outcomes for active drug versus placebo. Neutral responses were included with ratings of disagreement as follows: “strongly disagree/disagree/undecided vs. agree/strongly agree;” “very dissatisfied/mostly dissatisfied/neutral vs. mostly satisfied/very satisfied;” and “a lot better/a little better vs. about the same/a little worse /a lot worse.” Outcomes were compared using an extended Chi-square test or an extended Fisher’s exact test as appropriate. For all comparisons, p<0.05 was considered significant. Statistical analyses were performed using STATA Version 14.2 (College Park, TX, USA). Missing data were omitted from analyses by individual outcome. Qualitative data were interpreted utilizing inductive coding to identify salient themes

3.0. Results

3.1. Baseline characteristics

Only 57 of the 83 participants were offered enrollment into the acceptability survey sub-study (18 placebo, 39 DMAU) due to delayed implementation of the questionnaire; 100% (57/57) of potential respondents enrolled, completed and returned the surveys. Acceptability survey participants were generally older than 25 (mean 30; median 28 years), sexually active (75%), non-Hispanic (82%), White (51%), never married (75%), and educated (63% had at least graduated from college) (Table 1). The demographic distribution of the acceptability sub-study did not differ from those participating in the main study. Nearly half the participants reported that they were in long-term, sexually active relationships (married, co-habitating, or steady partnership). Approximately half of the participants had used male condoms alone or in combination with a female contraceptive (53%) both during and in the month before enrollment in the study. Few participants (4%) reported dissatisfaction with previously used methods.

Table 1.

Baseline demographics and contraceptive use among male study participants randomized to 28 days of daily active drug (dimethandrolone undecanoate, DMAU) vs. placebo, in a phase 1 HMC trial.

Survey Respondent Characteristics		Drug n = 39 (%)	Placebo n = 18 (%)	All n = 57 (%)
Race	American Indian/Alaskan Native	0 (0.0)	1 (5.6)	1 (1.8)
	Asian	7 (18.0)	3 (16.7)	10 (17.5)
	Black	6 (15.4)	2 (11.1)	8 (14.0)
	White	19 (48.7)	10 (55.6)	29 (50.9)
	Other	7 (18.0)	2 (11.1)	9 (16.8)
Ethnicity	Non-Hispanic	34 (87.2)	13 (72.2)	47 (82.5)
	Hispanic	5 (12.8)	5 (27.8)	10 (17.5)
Education	Less than 12 years	1 (2.6)	0 (0.0)	1 (1.8)
	High school graduate	3 (7.7)	0 (0.0)	3 (5.3)
	Some college	11 (28.2)	6 (33.3)	17 (29.8)
	College graduate	16 (41.0)	11 (61.1)	27 (47.4)
	Masters or doctoral level	8 (20.5)	1 (5.6)	9 (15.8)
Marital status	Married	5 (12.8)	2 (11.1)	7 (12.3)
	Never married	28 (71.8)	15 (83.3)	43 (75.4)
	Separated/divorced	6 (15.4)	1 (5.6)	7 (12.3)
Sexual relationship	Not sexually active	12 (30.8)	2 (11.1)	14 (24.6)
	Married	2 (5.1)	3 (16.7)	5 (8.8)
	Co-habitating	4 (10.3)	2 (11.1)	6 (10.5)
	Steady partner	9 (23.1)	6 (33.3)	15 (26.3)
	Casual partner	8 (20.5)	3 (16.7)	11 (19.3)
	Other/unanswered	4 (10.3)	2 (11.1)	6 (10.5)
Contraceptive use in the month before and during the trial	Condom (male or female)	16 (41.0)	8 (44.4)	24 (42.1)
	Female, short-acting, reversible*	3 (7.7)	2 (11.1)	5 (8.8)
	Female, (LARC)**	2 (5.1)	0 (0.0)	2 (3.5)
	Dual method use***	4 (10.3)	2 (11.1)	6 (10.5)
	None/rhythm/withdrawal	13 (33.3)	6 (33.3)	19 (33.3)
	Don’t Know	1 (2.6)	0 (0.0)	1 (1.8)
Satisfaction with current contraceptive	Dissatisfied/very dissatisfied	2 (5.3)	0 (0.0)	2 (3.6)
	Neutral or mixed	3 (7.9)	6 (33.3)	9 (16.1)
	Very satisfied/satisfied	33 (86.8)	12 (66.7)	45 (80.4)

^†No significant difference in the distribution of drug vs. placebo across respondent characteristics (p < 0.05).

^*Female, short-acting contraceptives: cervical cap, female condom, diaphragm, sponge, oral pill, patch.

^**Female long-acting contraceptive (LARC): intrauterine device (IUD), implant.

^***Dual method: any female method plus male condom.

3.2. User experience

Nearly all participants reported satisfaction with receiving clear instructions on how to take the capsules (55/57, 97%), and the ease of taking several capsules at the same time each day (47/57, 83%) (Table 2). Nearly all reported that the capsules were easy to swallow (53/57, 93%) and easy to take on a full stomach (53/57, 93%). Few participants (<10%) reported any difficulties with the capsules, such as an unpleasant taste or texture, or breakage or leakage. Nearly one-third (16/57, 28%) of participants reported difficulty with adherence to the fat content required in a meal prior to capsule ingestion. There were eight individuals reporting problems with the capsules or administration regimen: too much fat (5), did not eat breakfast (2) and uncertainty on how much to eat (1). However only six (75%) reported that these problems would preclude long-term use of the study drug, and only three (38%) reported that requiring a high-fat meal prior to capsule administration would be unacceptable (and prevent long-term continuation of the study drug). Participants were not explicitly asked about difficulties with the number of capsules that they were required to ingest daily. However, those receiving four capsules (5/21, 24%) were more likely to report they would stop using the method compared to those receiving two capsules (1/18, 6%; p= 0.04)

3.3. Overall Acceptability

Most (45/57; 79%) respondents were satisfied overall with the trial drug formulation (Table 3); 25/45 agreed and 20/45 strongly agreed that they were satisfied overall. More than half (31/57, 54%) would use the trial drug as their primary contraceptive if available today; 13/31 (42%) agreed and 18/31 (58%) strongly agreed. Most (43/57, 77%) would recommend this method to others; 23/43 (53%) agreed and 20/43 (47%) strongly agreed. Nearly half (25/57, 45%) of the respondents reported their experience as better than expected, and only 4/57 (7%) participants rated their experience as worse or slightly worse than expected (Table 3). There were only a small number of participants who reported issues whilst taking the study drug; these included acne (1), lower sex drive/libido (1), the inconvenience of taking 4 capsules (1) and weight gain (1). There was no association with an overall worse experience in this group and no respondent expressed any extreme negative experience.

All participants were advised the study method was investigational and would not prevent pregnancy or the transmission of STIs. As condoms are the only effective method for STI prevention, participants were also asked about condom use. In those who were sexually active, 22/41 (54%) reported using condoms in the month prior to enrollment, and among these condom users, 19/22 (86%) reported that prevention of STIs was an important consideration in their contraceptive choice. However, when asked to rate their experience using the study drug more than half of condom users (14/22; 64%;) reported a better than expected experience and nearly half of condom users (10/22; 45%;) would be willing to use the study method as their primary form of contraception if available.

The primary reason given by participants for study enrollment was the desire to contribute to research and the advancement of male contraception (53%). Three male subjects expressed a preference for a (hormonal) male contraceptive, one of whom commented, “I wanted to take male contraception because my girlfriend does not use birth control and is allergic to condoms.” Another individual reported interest in promoting gender equity in family planning, stating, “I feel strongly that a birth control pill is exceedingly important technology. It will give women greater freedom and men greater responsibility. I am deeply grateful to participate in the development of this technology in whatever way I can.”

3.4. Drug versus placebo group

The acceptability of active drug was similar to the placebo, except active drug group participants were more likely to report overall satisfaction with the study drug than placebo group participants (33/39, 87% vs. 12/18, 67%; p=0.05). In addition, participants in the active group were more likely to affirm that “it was easy to take them at the same time each day” (35/39, 90% vs. 12/18, 67%; %, p=0.03). More participants were “undecided” in the placebo group than active group (6/18; 33% vs. 3/39; 8%) (Table 3).

4.0. Discussion

The majority of respondents rated the daily oral regimen (oral DMAU vs. placebo) as an acceptable and satisfactory potential contraceptive across several measures. Furthermore, most respondents rated this method as superior to the method used in the month before enrollment in this study. This did not differ significantly between active drug and placebo groups nor by prior contraceptive method.

The overall acceptability in the active and placebo groups in this study is high and comparable to levels of acceptability reported in other HMC trials including: an injection-only hormonal male contraceptive regimen [3], a combination of daily transdermal testosterone gel and intramuscular depot medroxyprogesterone acetate administered every three months [17], and a six-month trial of testosterone and nesterone topical gels applied daily [5]. Over half of respondents in our DMAU study indicated that they would use this once-daily oral regimen as their primary method of contraception if DMAU were available, a finding similar to that of other HMC studies [5, 17]. Unlike other HMC studies of acceptability, our study included a placebo group to remove any potential treatment effect in the assessment of the acceptability of taking a daily male pill. Furthermore, participants randomized to active DMAU were significantly more likely than those receiving placebo to report that the capsules were easy to use consistently supporting that an oral daily HMC would likely be acceptable to men.

The consumption of a high fat meal before taking oral DMAU was not a significant drawback; only three participants (7%) indicated they would have discontinued long-term use due to this reason. The need for concomitant ingestion of food on absorption of DMAU will be the subject of future studies. A high proportion of the participants (83%) reported no issues with adherence, acceptability or satisfaction of 2 compared with 4 capsules daily. Interestingly, although participants indicated that STI prevention was an important characteristic for HMC, the study method’s intended provision of contraception (without STI prevention) neither influenced their overall satisfaction with the study drug nor their preference for its use as primary contraception if available, as compared to the contraceptive method used prior to entering the trial.

Our study has several strengths, including inclusion of a placebo group, a broad range of assessments for acceptability, satisfaction, and tolerability, as well as a prospective design. Limitations of our study include a short treatment period and small sample size. With only 28 days of drug exposure, participants might not have developed or detected side effects. In addition, our results are biased by the characteristics of the study cohort. Men who are healthy and motivated to enroll in a trial aimed to develop a hormonal male contraceptive might not represent the general population of men. Importantly, participants in this trial were not relying on the study product for contraception; whether that might have influenced their attitudes towards acceptability is not known. Finally, partners of participants were not surveyed, which would have given valuable information about female partners’ willingness to rely on a male partner to use a once-daily oral regimen.

In conclusion, this placebo-controlled study demonstrates that an oral HMC formulation is likely to be acceptable to most men. Overall acceptability of once-daily DMAU was high, and over one-half of men reported they would use oral DMAU as their primary form of contraception if it were commercially available. The dietary requirements for the delivery system did not lower adherence or acceptability. Population growth and diminishing resources require innovation in the family planning sphere [20] and some models suggest novel male methods could be impactful [1]. Reversible, reliable, and acceptable oral HMC would be an important addition to current contraceptive options. The results from this trial provide a strong rationale for further evaluation of DMAU, and other novel oral male contraceptive agents.