Pharmacodynamics and Safety of Human Recombinant LH in HH Men

[madman]

Acquired Hypogonadotropic Hypogonadism Trial in Italy (Lutropin alfa, Human chorionic gonadotropin) | Clincosm

Recruiting. Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men

www.clincosm.com

STUDY DESCRIPTION

Brief Summary

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 fixed dose of hCG, and later for a 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 fixed 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 tumors 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 the two-weekly intervals, 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.

AT V1 PATIENTS WILL BE RANDOMIZED INTO TWO DIFFERENT GROUPS:​

Study group Control group

The study group will receive the daily administration sc of Luveris with increasing dosages every two weeks (Treatment phase) as follows:

1. Rec-LH 75 IU daily for 2 weeks;
2. Rec-LH 150 IU daily for 2 weeks;
3. Rec-LH 300 IU daily for 2 weeks;
4. Rec-LH 600 IU daily for 2 weeks. The decision to proceed to the next dose level of LH will be made by the Study Team [and the investigator] based on safety, tolerability, and preliminary data obtained in at least 5 participants at the prior dose level. If moderate or severe AE is consistently observed across participants in a cohort or if unacceptable pharmacological effects, reasonably attributable to LH in the opinion of the investigator are observed in more than 15% of the participants in a cohort, then dose escalation will be temporarily halted and no further participants will be dosed until a full safety review of the study has taken place. Relevant reporting and discussion with the Medical Monitor, PI, and the IRB/IEC will take place before the resumption of dosing.

The two months of treatment will be followed by one month of treatment wash-out (follow-up phase).

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. Hypopituitary patients participating in the study will continue to receive their standard substitution therapy in as much needed (thyroxine, hydrocortisone). During the study duration, androgen replacement therapies will be not permitted.

 

[DS3]

Acquired Hypogonadotropic Hypogonadism Trial in Italy (Lutropin alfa, Human chorionic gonadotropin) | Clincosm

Recruiting. Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men

www.clincosm.com

STUDY DESCRIPTION

Brief Summary

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 fixed dose of hCG, and later for a 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 fixed 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 tumors 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 the two-weekly intervals, 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.

AT V1 PATIENTS WILL BE RANDOMIZED INTO TWO DIFFERENT GROUPS:​

Study group Control group

The study group will receive the daily administration sc of Luveris with increasing dosages every two weeks (Treatment phase) as follows:

1. Rec-LH 75 IU daily for 2 weeks;
2. Rec-LH 150 IU daily for 2 weeks;
3. Rec-LH 300 IU daily for 2 weeks;
4. Rec-LH 600 IU daily for 2 weeks. The decision to proceed to the next dose level of LH will be made by the Study Team [and the investigator] based on safety, tolerability, and preliminary data obtained in at least 5 participants at the prior dose level. If moderate or severe AE is consistently observed across participants in a cohort or if unacceptable pharmacological effects, reasonably attributable to LH in the opinion of the investigator are observed in more than 15% of the participants in a cohort, then dose escalation will be temporarily halted and no further participants will be dosed until a full safety review of the study has taken place. Relevant reporting and discussion with the Medical Monitor, PI, and the IRB/IEC will take place before the resumption of dosing.

The two months of treatment will be followed by one month of treatment wash-out (follow-up phase).

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. Hypopituitary patients participating in the study will continue to receive their standard substitution therapy in as much needed (thyroxine, hydrocortisone). During the study duration, androgen replacement therapies will be not permitted.





View attachment 15403

When this study’s results are complete, please post them. This is extremely interesting.

 

[DS3]

@madman Are you aware if Luveris is commercially available?

 

[madman]

@madman Are you aware if Luveris is commercially available?

It is mainly used in women for treating hormone deficiencies/infertility.

The active substance in Luveris (lutropin alfa) is a copy of the natural hormone LH.

Even if it could be prescribed off-label for use in men highly doubtful it would be cost-effective long-term.



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 fixed dose of hCG, and later for a more extend steroid profile.




DETAILED DESCRIPTION

Primary endpoint

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 endpoint is serum testosterone levels in response to increasing doses of LH (pharmacodynamics) and the comparison of the response to a fixed dose of hCG. The statistical hypothesis is non-inferiority of the highest LH dose compared to the fixed hCG dose employed.


Secondary endpoints

1. Full Safety profile (see below, the appropriate paragraph).
2. 
   
3. 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.
4. 
   
5. 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 a 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 signaling 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 the 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.
6. 
   
7. 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 characterize the LH pharmacodynamics in men, compared to the standard approach, represented by hCG administration, and to evaluate rLH safety profile.

The center 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 center. Moreover, Unit 1 will perform centralized hormone measurements at the end of the study, will coordinate monitoring of centers, will maintain the study database, and will analyze the data collected. Finally, the pharmacy at Unit 1 will receive IMP and will buy the drug comparator, will package and distribute drugs needed for the study.

Patients will be screened according to inclusion and exclusion criteria at each Centre.




DURING THE SCREENING VISIT, THE FOLLOWING EVALUATIONS WILL BE PERFORMED:

EVALUATIONS AT THE PARTICIPATING CENTRE:​

Total testosterone serum levels; Basal hormonal and biochemical assays needed to fulfill inclusion and exclusion criteria;

SCROTAL ULTRASOUND FOR THE EVALUATION OF:​

varicocele presence and degree; testicular volume and structure; epididymis. All other imaging analyses needed to fulfill inclusion and exclusion criteria, as well as suggested by the guidelines for pituitary diseases (Raverot, Burman, et al. 2018).

CENTRAL EVALUATIONS AT UNIT 1:​

Total testosterone serum levels, using LC-MS/MS; Progesterone,17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), corticosterone, 11-deoxycortisol and cortisol using LC-MS/MS by a validated method (Fanelli, Belluomo, et al. 2011); Other hormonal analyses.

Eligible patients will be enrolled in the study after signing the informed consent. Eligible patients that are under androgen replacement therapy at the time of screening visit will be enrolled after three months of testosterone withdrawal. On the contrary, eligible patients who are not treated at the time of screening visit will be immediately enrolled.

At Visit 1 (V1), patients will be randomized according to the randomization list centrally provided and will be allocated to the two following groups:

Study group; Control group.

AT EACH VISIT THE FOLLOWING EVALUATIONS WILL BE PERFORMED:​

EVALUATIONS AT PARTICIPATING CENTRE:​

Total testosterone serum levels Safety profile (as elaborated below) Basal hormonal and biochemical assays Central evaluations at Unit 1:Total testosterone serum levels, using LC-MS/MS Other sex steroids using LC-MS/MS Other hormonal analyses Biochemical evaluations performed at each center will be useful to monitor the treatment efficacy and safety, whereas centrally performed analyses will be used for the final statistical analysis. Moreover, at the end of the treatment phase (V16) and at the end of the follow-up phase, scrotal ultrasound will be repeated to address possible morphological changes related to an endogenous testosterone increase. Finally, at each visit, the occurrence of AESI will be properly registered and reported. Pharmacovigilance will be carefully considered and evaluated by CRO. During each visit, testosterone levels were performed locally and evaluated by clinicians. Whether testosterone serum levels will reach levels higher than 12 nmol/L, the drug dosage will be not increased in both groups. The hormonal results will be available in about 8 hours.




*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.




The aim of the study is the evaluation of LH pharmacodynamics in HH men, in terms of testosterone serum levels increase and to evaluate rLH safety profile. Considering the only one case available in the literature, in which LH and hCG were compared in a HH man, the hypothesis is a non-inferiority between IMP (at least at the highest dose) and comparator.


There is a practical and scientific reason for the choice of the drug and the methodology proposed. Concerning r-hLH, Luveris is the only LH approved for human use. The dosage was chosen according to the literature evidences of the different actions of LH and hCG at the molecular level and in vivo in women (Santi, Casarini, et al. 2017). The dosage and the frequency of administration were chosen according to the only previous experience existing and considering the half-life of LH. Daily injections are appropriate because clinical practice in women undergoing ART or with HH demonstrates the efficacy of LH daily protocols. In The investigator's previous experience, LH was administered as a single daily bolus, reaching a significant testosterone increase. The investigators considered that physiological LH secretion is pulsatile. Veldhuis et al., compared constant to pulsatile infusion of r-hLH in 19 healthy men previously treated with GnRH antagonist. These two LH administration patterns reached a similar testosterone increase, suggesting that pulsatile LH administration is not necessary to stimulate Leydig cells activity. Moreover, in this clinical trial, a daily LH dosage of 112.5 IU resulted in maximum testosterone levels of 485+114 ng/dl, in the physiological range. Similarly, in the investigator's case report, the HH man was treated with 75 IU of daily LH, restoring eugonadism. Thus, much lower LH dosages than expected seem to be sufficient to increase testosterone serum levels into the normal range. Therefore, the investigators will test different LH dosages, starting from the expected minimum efficient dosage (75 IU), to the maximum dosage (600 IU) expected to obtain testosterone serum levels in the UPPER HALF of normal ranges.

*The comparator (Gonasi HP) type and dosage was chosen according to the literature, the rationale provided above, according to the current standard of treatment, and the fact that it is the only hCG preparation approved for use in male HH available in Italy at the moment








ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action LUVERIS, a recombinant human luteinizing hormone (r-hLH), is a heterodimeric glycoprotein consisting of two non-covalently linked subunits (designated α and β) of 92 and 121 amino acids, respectively. Luteinizing hormone binds to a receptor shared with the human chorionic gonadotropin hormone (hCG) on the ovarian theca (and granulosa) cells and testicular Leydig cells. This LH/CG transmembrane receptor is a member of the superfamily of G protein-coupled receptors. In vitro, the affinity binding of recombinant hLH to the LH/CG receptor on Leydig tumor cells (MA-10) is between that for hCG and that of pituitary hLH, but within the same order of magnitude.

In the ovaries, during the follicular phase, LH stimulates theca cells to secrete androgens, which will be used as the substrate by granulosa cell aromatase enzyme to produce estradiol, supporting FSH-induced follicular development. At mid-cycle, high levels of LH trigger corpus luteum formation and ovulation. After ovulation, LH stimulates progesterone production in the corpus luteum by increasing the conversion of cholesterol to pregnenolone. In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from the administration of lutropin alfa is an increase in estradiol secretion by the follicles, the growth of which is stimulated by follitropin alfa.

Following intramuscular administration, LUVERIS exhibits absolute bioavailability of 0.54 and a terminal half-life of 16 hours. The longer time for elimination from the body with intramuscular dosing compared to intravenous indicates that absorption may be a rate-limiting factor. Following subcutaneous administration, the absolute bioavailability is 0.56; the terminal half-life is slightly prolonged (mean=21h) compared to IM. The lutropin alfa pharmacokinetics following single and repeated administration of LUVERIS are comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.




Pharmacokinetics

Following intravenous administration, LUVERIS is rapidly distributed with an initial half-life of approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours. The steady-state volume of distribution is around 10-14 L. When given by intravenous administration, LUVERIS demonstrates linear pharmacokinetics over higher doses (300 to 40,000 IU). However, following administration of the lower dose (75 IU), the concentration range is too small to allow proper quantification of the pharmacokinetic parameters. The disposition of r-hLH is adequately described by a biexponential model. Total clearance is around 2 L/h, and less than 5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours. Following subcutaneous administration, the absolute bioavailability is 0.56. The lutropin alfa pharmacokinetics following single and repeated administration of LUVERIS is comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.

 

[madman]

When this study’s results are complete, please post them. This is extremely interesting.

Definitely looking forward to this!




Anticipated Study Start Date: Oct 1, 2021

Anticipated Study Completion: Oct 1, 2023

OUTCOME MEASURES​

PRIMARY OUTCOME MEASURES​

1. Testosterone [2 weeks after treatment start]
   total testosterone serum levels
2. Testosterone [4 weeks after treatment start]
   total testosterone serum levels
3. Testosterone [6 weeks after treatment start]
   total testosterone serum levels
4. Testosterone [8 weeks after treatment start]
   total testosterone serum levels

SECONDARY OUTCOME MEASURES​

1. Inhibin B [2 weeks after treatment start]
   Inhibin B serum levels
2. Inhibin B [4 weeks after treatment start]
   Inhibin B serum levels
3. Inhibin B [6 weeks after treatment start]
   Inhibin B serum levels
4. Inhibin B [8 weeks after treatment start]
   Inhibin B serum levels
5. Free testosterone [2 weeks after treatment start]
   Free testosterone serum levels
6. Free testosterone [4 weeks after treatment start]
   Free testosterone serum levels
7. Free testosterone [6 weeks after treatment start]
   Free testosterone serum levels
8. Free testosterone [8 weeks after treatment start]
   Free testosterone serum levels
9. SHBG [2 weeks after treatment start]
   sex hormone-binding globulin (SHBG)
10. SHBG [4 weeks after treatment start]
    sex hormone-binding globulin (SHBG)
11. SHBG [6 weeks after treatment start]
    sex hormone-binding globulin (SHBG)
12. SHBG [8 weeks after treatment start]
    sex hormone-binding globulin (SHBG)
13. Estradiol [2 weeks after treatment start]
    Estradiol serum levels by LC-MS/MS evaluation
14. Estradiol [4 weeks after treatment start]
    Estradiol serum levels by LC-MS/MS evaluation
15. Estradiol [6 weeks after treatment start]
    Estradiol serum levels by LC-MS/MS evaluation
16. Estradiol [8 weeks after treatment start]
    Estradiol serum levels by LC-MS/MS evaluation
17. LH [2 weeks after treatment start]
    Serum LH
18. LH [4 weeks after treatment start]
    Serum LH
19. LH [6 weeks after treatment start]
    Serum LH
20. LH [8 weeks after treatment start]
    Serum LH
21. FSH [2 weeks after treatment start]
    Serum FSH
22. FSH [4 weeks after treatment start]
    Serum FSH
23. FSH [6 weeks after treatment start]
    Serum FSH
24. FSH [8 weeks after treatment start]
    Serum FSH

OTHER OUTCOME MEASURES​

1. Steroids [2 weeks after treatment start]
   Other steroids provided by the LC-MS/MS methodology
2. Steroids [4 weeks after treatment start]
   Other steroids provided by the LC-MS/MS methodology
3. Steroids [6 weeks after treatment start]
   Other steroids provided by the LC-MS/MS methodology
4. Steroids [8 weeks after treatment start]
   Other steroids provided by the LC-MS/MS methodology
5. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [2 weeks after treatment start]
   This was evaluated considering red blood cell count, marker of liver function, markers of coagulation.
6. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [4 weeks after treatment start]
   This was evaluated considering red blood cell count, marker of liver function, markers of coagulation.
7. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [6 weeks after treatment start]
   This was evaluated considering red blood cell count, marker of liver function, markers of coagulation.
8. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [8 weeks after treatment start]
   This was evaluated considering red blood cell count, marker of liver function, markers of coagulation.
9. Testicular volume [Baseline]
   The testicular volume will be assessed locally at each visit by a physician blind to the patient group allocation
10. Testicular volume [8 weeks after treatment start]
    The testicular volume will be assessed locally at each visit by a physician blind to the patient group allocation.