| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypoactive Sexual Desire Disorder/SSRI-induced sexual dysfunction |
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| E.1.1.1 | Medical condition in easily understood language |
| Lack of sexual desire/sexual complaints caused by use of antidepressants |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Psychological processes [F02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10040470 |
| E.1.2 | Term | Sexual desire disorders |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020933 |
| E.1.2 | Term | Hypoactive sexual desire disorder |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To validate the existing diagnostic model which predicts the sensitivity to Lybrido or Lybridos in women with HSDD (with or without FSAD and/or FOD as secondary diagnosis), measured by the number of satisfactory sexual events.
• To identify additional psychometric and biological markers for the diagnostic model in order to increase predictive power for sensitivity to Lybrido or Lybridos in women with HSDD (with or without FSAD and/or FOD as secondary diagnosis), measured by the number of satisfactory sexual events.
• To evaluate/validate the altered diagnostic model in women with HSDD (with or without FSAD and/or FOD as secondary diagnosis), measured by the number of satisfactory sexual events.
• To identify psychometric and biological markers to predict the sensitivity to Lybrido or Lybridos in women with SSRI-induced sexual dysfunction, measured by the number of satisfactory sexual events.
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| E.2.2 | Secondary objectives of the trial |
• To identify the optimal dose of Lybridos (Lybridos-10 vs Lybridos-20) in women with HSDD (with or without FSAD and/or FOD).
• To identify the optimal dose of Lybridos (Lybridos-10 vs Lybridos-20) in women with SSRI induced sexual dysfunction.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent
2. Females between 18 and 70 years of age, inclusive, pre or postmenopausal, with HSDD or SSRI induced sexual dysfunction (comorbidity with female sexual arousal disorder [FSAD] and/or female orgasmic disorder [FOD]; only as secondary diagnosis) is allowed. The diagnosis of HSDD or SSRI induced sexual dysfunction will be established by a trained health care professional
3. Be involved in a stable, communicative, monogamous relationship and have a sexually functional partner who will be at home for the majority of the study duration
4. Healthy with normal medical history, physical examination, laboratory values, and vital signs; exceptions may be made if the investigator considers an abnormality to be clinically irrelevant
5. Use of highly effective contraception
6. For women who use SSRI: usage of an SSRI for the treatment of anxiety disorders or depression (not for, for example, anorexia nervosa or obsessive compulsive disorder) for a minimum of 3 months and on a stable dose for at least 6 weeks before screening. The following dosage ranges are allowed: Prozac (fluoxetine) 20-80 mg/day; fluvoxamine 100-300 mg/day; Zoloft (sertraline) 50-200 mg/day; Paxil (paroxetine) 20-60 mg/day; Celexa (citalopram) 20-40 mg/day; Lexapro (escitalopram) 10-30 mg/day
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| E.4 | Principal exclusion criteria |
1. Any underlying cardiovascular condition, including unstable angina pectoris, that would preclude sexual activity
2. Systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg (supine blood pressure). For subjects ≥ 60 years old and without diabetes mellitus, familial hypercholesterolemia, or cardiovascular disease: systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 90 mmHg
3. Systolic blood pressure ≤ 90 mmHg and/or diastolic blood pressure ≤ 50 mmHg (supine blood pressure).
4. Use of any contraceptive containing anti-androgens or (anti)androgenic progestogens (drospirenone, dienogest, chlormadinone acetate and norgestrel)
5. Use of any contraceptive or hormone replacement therapy (HRT) containing more than 50 μg/day of estrogen
6. Pregnancy or intention to become pregnant during this study
7. Lactating or delivery in the previous 6 months prior to signing Informed Consent Form
8. History of bilateral oophorectomy
9. Other unexplained gynecological complaints, such as clinically relevant abnormal uterine bleeding patterns
10. Perimenopausal status (cycle shortening/irregular menstrual bleeding in the last 12 consecutive months and/or occurrence of vasomotor symptoms and/or FSH levels (>40 IU/L) for women from age 40 onwards; in women with a history of hysterectomy perimenopausality can be assessed by FSH levels (> 40 IU/L) and/or vasomotor symptoms)
11. Liver and/or renal insufficiency (aspartate aminotransferase, alanine aminotransferase and gamma glutamyltransferase > 3 times the upper limit of normal and/or estimated glomerular filtration rate (eGFR) < 60.00 mL/min based on the Cockcroft Gault formula)
12. Any current endocrine disease or endocrinopathy as determined by medical history, basic physical examination and/or laboratory values significantly outside normal range of the central laboratory; or uncontrolled diabetes mellitus(HbA1c > 7.5%)
13. Free- and/or total testosterone levels outside the upper limit of the reference range of the central laboratory (free testosterone: > 1.1 ng/dL, and total testosterone > 80 ng/dL)
14. Any current clinically relevant neurological disease which, in the opinion of the investigator, would compromise the validity of study results or which exclude from use of sildenafil, buspirone and/or testosterone
15. History of hormone dependent malignancy (including all types of breast cancer)
16. Positive test result for immunodeficiency virus, hepatitis B, or hepatitis C (acute and chronic hepatitis infection)
17. History of serotonin syndrome
Psychological/Psychiatric Factors
18. History of (childhood) sexual abuse that, in the opinion of the investigator, could result in negative psychological effects when testosterone is administered
19. (Psychotherapeutic and/or pharmacological treatment for) a psychiatric disorder (other than those under inclusion criterion 6) that, in the opinion of the investigator, would compromise the validity of study results or which could be a contraindication for sildenafil, buspirone and/or testosterone use
20. Current psychotherapeutic treatment for female sexual dysfunction
21. Current sexual disorder of vaginismus or dyspareunia according to the DSM IV TR, Anorgasmia with a lifelong inability to reach an orgasm
22. A substance abuse disorder that, in the opinion of the investigator, is likely to affect the subject's ability to complete the study or precludes the subject’s participation in the study
23. For women who use SSRI: for A score of ≥ 29 at the BDI II questionnaire. A score between 20-28 at the BDI-II when in the opinion of the psychologist the depressive symptoms interfere with sexual functioning or would otherwise compromise the validity of the study results.
24. A score of > 65 at the STAI-Y2 questionnaire
Concomitant Medications
25. Use of potent CYP3A4 inhibitors
26. Use of potent CYP3A4 inducers
27. Use of potent CYP2D6 inhibitors
28. Use of potent CYP2D6 inducers
29. Use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, or other anticoagulants
30. Use of tricyclic antidepressants or other antidepressants than SSRIs
31. Use of any other medication that interferes with study medication
32. Use of medication (including herbs) that would compromise the validity of study results
33. Use of testosterone therapy within 6 months before study entry prior to signing the Informed Consent Form
34. Use of any kind of benzodiazepines
35. Illiteracy, unwillingness, or inability to follow study procedures
36. Participation in other clinical trials within the last 30 days
37. Any other clinically significant abnormality or condition which, in the opinion of the investigator, might interfere with the participant’s ability to provide informed consent or comply with study instructions, compromise the validity of study results, or be a contraindication for buspirone, and/or sildenafil and/or testosterone use
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the number of satisfactory sexual episodes, measured using the Sexual Satisfaction of an Event Questionnaire (SSEQ).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Sexual satisfaction
o SSEQ
Sexual desire/arousal
o Sexual Anamnesis Questionnaire-Improvement (SAQ I)
o Sexual Function Questionnaire (SFQ)
o Weekly diary
Subjective evaluation of gain and improvement
o Subjective Evaluation of Gain (SEG) questionnaire
o Subjective Evaluation of Improvement (SEI) questionnaire
Sexual Distress
o Female Sexual Distress Scale –revised (FSDS-R)
o Modified version of Sexual Anamnesis Questionnaire (SAQ)
Profile of mood state
o Profile of Mood State (POMS) questionnaire
Safety assessments
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All endpoints: End of study |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
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