E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypogonadotropic hypogonadism (HH) |
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E.1.1.1 | Medical condition in easily understood language |
Hypogonadotropic hypogonadism (HH) is a gonadotropin-releasing hormone deficiency which may cause obesity, low libido and infertility. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021012 |
E.1.2 | Term | Hypogonadotrophic hypogonadism |
E.1.2 | System Organ Class | 100000004860 |
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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 |
The primary objective is to demonstrate the efficacy of BGS649 to normalise total testosterone levels (300-1000 ng/dL [10.4-35 nmol/L]) in ≥ 75% of subjects after 24 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives
1. To follow the time-course of normalisation in total testosterone levels
2. To demonstrate the efficacy of BGS649 to normalise total testosterone levels in ≥ 90% of subjects after 24 weeks of treatment
3. To evaluate the effect of BGS649 on luteinising hormone (LH) and follicle stimulating hormone (FSH)
4. To further determine the pharmacokinetics (PK) of BGS649.
Safety Objectives:
1. To evaluate safety and tolerability of BGS649.
Exploratory Objectives:
1. To evaluate the effect of BGS649 on oestradiol, DHT and inhibins (A and B)
2. To evaluate the effect of BGS649 on testosterone/oestradiol ratio
3. To investigate patient reported outcomes (PROs) following treatment with BGS649. Evaluated PROs will include:
- Sexual function (IIEF & PROMIS SexFS)
- Energy/fatigue (Brief Fatigue Inventory [BFI])
- SF-36 Quality of life (QoL) questionnaire
- Patient Global Impression (PGI-S)
For additional Exploratory Objectives refer to the protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult male subject aged 18 to 65 years inclusive
2. BMI > 30 kg/m2 and < 50 kg/m2
3. Serum total testosterone concentration below the normal range (serum total testosterone < 300 ng/dL [< 10.4 nmol/L]) in both of two morning samples, taken before 11:00 am, at least 3 days apart
4. LH levels below the upper limit of normal (ULN)
5. Oestradiol levels within or above the normal range of approved assay
6. At least two symptoms of androgen deficiency present for at least 2 months prior to the first Screening Visit, with at least one of these being a sexual dysfunction
7. Agreement on the part of the subjects to use double-barrier contraception for vaginal sexual intercourse with female partners of child bearing potential to prevent conception and theoretical fetal risk of BGS649 exposure from seminal fluid. To use single barrier protection (condom) to prevent semen exposure through non-vaginal sexual intercourse with female partners of child bearing potential and refrain from sperm donation for the duration of the study. All to be continued for at least 3 months following study drug discontinuation.
8. Ability to understand and comply with the requirements of the protocol/study, including understanding and being able to give informed consent. |
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E.4 | Principal exclusion criteria |
1. Evidence of clinically significant endocrinopathy at Screening that may interfere with the study assessments or mask/mimic symptoms of hypogonadism e.g., growth hormone deficiency, adrenal deficiency, untreated hypothyroidism (primary hypothyroidism on replacement with normal thyroid stimulating hormone [TSH] level is allowed), or that may interfere with the evaluation of efficacy/safety parameters
2. Other types of HH (e.g., Kallmann syndrome) or primary hypogonadism (e.g., cryptorchidism, or Klinefelter syndrome)
3. Any other pituitary or hypothalamic disease, as based on one of the following:
- Current or past hypothalamic or pituitary tumour
- Suspicion of pituitary or hypothalamic tumour based on a clinical or laboratory evidence, e.g., elevated prolactin or other pituitary hormone abnormality, symptoms/signs of tumour mass effect, very low testosterone and LH (unless there is documentation of a normal magnetic resonance imaging scan of pituitary and hypothalamus within 3 months before first Screening Visit)
- Hypothalamic or pituitary conditions, which may contribute to hypogonadism e.g., pituitary sarcoidosis, histiocytosis or tuberculosis
4. Subject with prostate disease, as confirmed by the presence of one of the following:
- History of prostate cancer
- Elevated PSA levels ≥ 3 ng/mL at Screening
- Subjects with a detectable prostate nodule or induration at Screening unless proven previously benign by a biopsy
- Urologist confirmed symptomatic benign prostatic hyperplasia
5. History of type 1 diabetes mellitus
6. Current clinical diagnosis of depression or current or past Bipolar disorder
7. Uncontrolled type 2 diabetes mellitus (HbA1c > 10.5% at Screening) or significant diabetic neuropathy. Subjects with type 2 diabetes can be included when both of the following conditions are met:
- HbA1c ≤ 10.5% at Screening, and:
- Anti-diabetic medication regimen (excluding insulin) has been stable for ≥ 8 weeks before the first Screening visit
8. Treatment with one or more of the following prescribed or over the counter medications in the six months prior to first Screening Visit:
- Medications with known androgenic or estrogenic properties or known to affect production of sex hormones
- Injectable testosterone enhancement therapy
- Fertility drugs
- Growth hormone
- Anabolic steroids
- Long acting opiates
9. Treatment with topical testosterone therapy in the two months prior to first Screening Visit
10. Treatment with one of the following medications for either >7 consecutive days in the three months prior to first Screening Visit OR any treatment within 3 weeks of first Screening Visit:
- Testosterone lowering drugs e.g., spironolactone, cimetidine, 5α-reductase inhibitors
- Short acting opiates / opioids including methadone
- Medications known to increase prolactin levels, e.g., antipsychotics
11. Treatment with the following medications:
- Chronic systemic steroid treatment or systemic steroids for > 5 consecutive days for intercurrent illness within the 4 weeks prior to the first Screening visit (inhaled and topical steroids are allowed)
- Clomid within 1 year before first Screening Visit
- Biphosphonates or other medication used to treat low bone density (denosumab, teriparatide) except calcium and vitamin D within 1 year before first Screening Visit
12. Weight loss or weight gain (gain or loss > 5% body weight) OR weight reduction surgery or procedure within the 3 months prior to first Screening Visit
13. Participation in any clinical trial using clinical investigational product intervention within 3 months before first Screening Visit or 5 half-lives of investigational product administration, whichever is longer
14. Any clinically significant 12-lead ECG abnormalities at Screening including corrected QT interval by Fridericia’s correction method (QTCF) > 450 ms
15. Medical history of Long QT syndrome
16. History of thromboembolic disease
17. Grade ≥ 3 lower extremity oedema
18. Use of cardiac pacemaker or other medical electronic devices that can be affected by bioimpedance assessment
Refer to the protocol for additional exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Normalisation of total testosterone levels in ≥ 75% of subjects at Week 24. |
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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) |
Secondary
1. Proportion of subjects that have normalisation of total testosterone to Week 24
2. Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dL [35 nmol/L]) to Week 24
3. Normalisation of total testosterone in ≥ 90% subjects to Week 24
4. Change of LH and FSH at 24 weeks
5. Population PK analysis of plasma BGS649 concentrations
6. PK analysis of semen BGS649 concentrations.
Exploratory
1. Change in oestradiol, inhibins (A and B) levels and DHT
2. Change in testosterone/oestradiol ratio
3. Body composition changes at Week 12 and Week 24
4. Changes in markers of cardiometabolic disease: blood pressure, lipid profile, HbA1c, glucose and insulin, hs-CRP and HOMA-IR and association with change in body composition and testosterone level.
5. Change in markers of bone turnover in those with and without 25 hydroxy vitamin D deficiency
6. Change in total and domain scores on PRO measures (IIEF, PROMIS SexFS: to assess sexual function; BFI, PROMIS Fatigue Short Form, SF-36 - Vitality: to assess energy levels and fatigue; SF-36: to assess general quality of life (QoL); PGI-S: to assess the patients’ impression of their current health status) over the 24 week period.
7. Change in physical activity, sleeping pattern and strength measured by wrist worn monitors and grip strength measurement at 12 and 24 weeks and association with body composition (as measured by BMI and waist circumference and impedance) and testosterone level.
8. PK/pharmacodynamic (PD) relationship between BGS649 concentrations and testosterone levels
9. For semen analysis: change in semen parameters throughout the study and association with LH/FSH level
10. Change in bioavailable testosterone
11. Time to first normal testosterone level.
Safety
1. Treatment emergent AEs (TEAEs)/SAEs (from first dose of study drug until 90 days after last treatment dose)
2. Change in PSA during 24 week treatment duration
3. Change in haematocrit during 24 week treatment duration
4. Change in Bone Mineral Density (DEXA scan T-score and density in g/cm3) from Screening and bone turnover biomarkers at 24-weeks from Baseline
5. Change in vital signs and clinical laboratory parameters, ECG
6. Change in physical examination (including general, prostate, breast and oedema of the lower extremities). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Italy |
Spain |
Sweden |
United Kingdom |
United States |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 10 |