Pharmacodynamics and Safety of Human Recombinant Luteinising Hormone in Hypogonadotropic Hypogonadal Men
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 32
- 试验地点
- 5
- 主要终点
- Testosterone
研究概览
简要总结
Objectives:
The overall clinical question is whether LH supplementation to men in indication for FSH according to the AIFA note 74, or with HH, will improve spermatogenesis and pregnancy rate (spontaneous or after ART) over FSH alone or FSH+hCG. However, since LH has never been used in men so far, the first, specific object of this study is the assessment of pharmacodynamics and safety profile of LH in HH men. To this end, this study will evaluate the pharmacodynamics and safety profile of recombinant LH (Luveris) and compare the response to Luveris and urinary hCG (Gonasi HP) in HH men. The pharmacodynamics will be assessed primarily for testosterone levels in response to increasing doses of LH and the comparison of the response to a fix dose of hCG, and later for more extend steroid profile.
Methods:
Multicentre longitudinal, interventional, randomized, open-label, phase II, clinical trial, assessing pharmacodynamics of LH in acquired HH men. The statistical hypothesis is non-inferiority of the highest LH dose employed compared to a fix hCG dose. Primary endpoint: serum testosterone levels evaluated by liquid-chromatography, tandem mass spectrometry (LC-MS/MS). Secondary endpoints: Safety and tolerability as determined by AE reporting, vital signs, and ECG, stereognosis (inhibin B, free testosterone, sex hormone binding globulin (SHBG), estradiol, whole steroid profile provided by LC-MS/MS) and testicular volume.
Patients: 32 men with acquired HH, including HH after neurosurgery for tumours or HH due to pituitary adenoma-related mass effect. Patients will be randomized (1:1) according to a permuted- blocks randomization list, to the study group, treated with Luveris (increasing doses at two weekly intervals), or to the control group treated with Gonasi HP (2000 IU twice/week). In the study group, increasing LH dosages will be administered to obtain a testosterone dose-response curve, starting with the minimum expected efficient dose (75 IU/d, sc) for two weeks followed by 150, 225 and 300 IU at two-weekly interval, respectively. The control group will be treated by the standard approach, i.e. hCG 2000 IU IM twice-weekly for 8 weeks. Patients will be further followed up for 4 weeks after treatment withdrawal. During the study, the patients will be evaluated two times per week during the treatment phase and every two weeks in the follow-up phase.
详细描述
Primary end point The pharmacodynamics of LH and the comparison of response to LH and hCG will be assessed by measuring serum steroid levels by liquid-chromatography, tandem mass spectrometry (LC-MS/MS). The primary end point is serum testosterone levels in response to increasing doses of LH (pharmacodynamics) and the comparison of the response to a fix dose of hCG. The statistical hypothesis is non-inferiority of the highest LH dose compared to the fix hCG dose employed.
Secondary end points
- Full Safety profile (see below, the appropriate paragraph).
- Identification of the LH dosages needed to restore normal testosterone production in men with acquired HH and of the relationship between LH administered and testosterone increase, e.g. in terms of % serum testosterone increase per IU of r-hLH. This parameter will be useful for future clinical studies based on LH.
- Comparison of steroid profiles, hormone related profiles and serum levels of testicular steroids upon stimulation by LH or hCG by immunoassay and by LC-MS/MS technique when available as validated method. The LC-MS/MS technique allows simultaneous detection and quantification of several steroids. The investigators have previously studied serum testicular steroid profiles in men with Klinefelter syndrome after acute hCG stimulation and in diabetic men chronically treated by a phosphodiesterase 5 inhibitor (Santi, Granata et al. 2017). In in vitro systems, the investigators showed that LH and hCG display biased signalling in Leydig cells, where LH is a partial agonist of the LHCGR on progesterone production, while hCG is a full agonist. However, both hormones were equivalent on testosterone production (Riccetti, Yvinec et al. 2017). This point is clinically relevant because progesterone is a pro-inflammatory hormone (Zitzmann, Erren et al. 2005). Should similarity of the two gonadotropins on testosterone production come together with higher progesterone secretion in the case of hCG, this finding might deserve further studies.
- Testicular size
Study design This is a multicentre, longitudinal, interventional, randomized, open-label, phase I/II, clinical trial. According to the study questions, the study is designed to characterise the LH pharmacodynamics in men, compared to the standard approach, represented by hCG administration and to evaluate rLH safety profile.
The centre at the PI site (Unit 1 - Modena) will coordinate the study and will prepare the randomization list by permuted blocks, which will be sent to each enrolling centre. Moreover, Unit 1 will perform centralized hormone measurements at the end of the study, will coordinate monitoring of centres, will maintain the study database and will analyse the data collected. Finally, pharmacy at Unit 1 will receive IMP and will buy the drug comparator, will package and distribute drugs needed for the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Age between 18 and 45 years
- •Acquired HH forms
- •HH after neurosurgery for tumors (i.e. pituitary adenoma, including prolactinoma, craniopharyngioma, germinomas, meningiomas, gliomas, and astrocytomas). Infiltrative disease (hemochromatosis, granulomatous disease, histiocytosis, and sarcoidosis), OR
- •HH due to pituitary adenoma-related mass effect, in case of cured or controlled hormone hypersecretion
- •Total testosterone serum levels below the normal ranges (lower than 3 ng/mL)
- •No androgen replacement therapies in the last three months before enrolment
- •No hyper-secretion of other pituitary hormones
排除标准
- •HH forms, such as:
- •Combined pituitary hormone deficiency
- •Genetic syndromes (e.g., Prader-Labhart-Willi, CHARGE, Lawrence-Moon- Bardet-Biedl)
- •Iatrogenic HH forms, such as traumatic pituitary stalk interruption syndrome, irradiation, high dose corticosteroids, and anabolic steroids
- •Drug abuse and major systemic diseases
- •Chronic severe liver disease
- •Concomitant illnesses which could interfere with the study participation
- •Active malignancy diseases
- •Known or possible androgen-dependent tumors for example male breast carcinoma or prostatic carcinoma
- •Cardiac failure, hypertension, renal dysfunction, migraines, or epilepsy. (since aggravation or recurrence may occasionally be induced as a result of increased androgen production)
- •Haematocrit <40% or >54%
- •Congenital HH are excluded since these genetic forms of HH could be related to other systemic or pituitary diseases, which could bias the selection of patients.
研究组 & 干预措施
Study group
The study group will receive the daily administration sc of Luveris with increasing dosages two weeks (Treatment phase) as follows: Rec-LH 75 IU daily for 2 weeks; Rec-LH 150 IU daily for 2 weeks; Rec-LH 300 IU daily for 2 weeks; Rec-LH 600 IU daily for 2 weeks.
干预措施: Lutropin alfa (Drug)
Control group
The control group will receive the administration im of Gonasi HP as follows:
hCG 500 IU two times weekly, for 2 weeks; hCG 1000 IU two times weekly, for 2 weeks; hCG 1500 IU two times weekly, for 2 weeks; hCG 2000 IU two times weekly, for 2 weeks.
干预措施: Human chorionic gonadotropin (Drug)
结局指标
主要结局
Testosterone
时间窗: 8 weeks after treatment start
total testosterone serum levels
次要结局
- Inhibin B(8 weeks after treatment start)
- Estradiol(8 weeks after treatment start)
- FSH(8 weeks after treatment start)
- Free testosterone(8 weeks after treatment start)
- SHBG(8 weeks after treatment start)
- LH(8 weeks after treatment start)
研究者
Daniele Santi
Assistant Professor
Azienda Ospedaliero-Universitaria di Modena