Ignite Creation Date:
2024-05-06 @ 2:00 PM
Last Modification Date:
2024-10-26 @ 1:23 PM
Study NCT ID:
NCT04189133
Status:
RECRUITING
Last Update Posted:
2023-07-20
First Post:
2019-11-29
Brief Title:
Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men
Sponsor:
Azienda Ospedaliero-Universitaria di Modena
Organization:
Azienda Ospedaliero-Universitaria di Modena
Study Overview
Official Title:
Pharmacodynamics and Safety of Human Recombinant Luteinising Hormone in Hypogonadotropic Hypogonadal Men
Status:
RECRUITING
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RHYTHM
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 FSHhCG 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-MSMS 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-MSMS 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 11 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 twiceweek 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 IUd 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 ie 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
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 FSHhCG 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-MSMS 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-MSMS 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 11 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 twiceweek 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 IUd 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 ie 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
Detailed Description:
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-MSMS 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
1 Full Safety profile see below the appropriate paragraph
2 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 eg in terms of serum testosterone increase per IU of r-hLH This parameter will be useful for future clinical studies based on LH
3 Comparison of steroid profiles hormone related profiles and serum levels of testicular steroids upon stimulation by LH or hCG by immunoassay and by LC-MSMS technique when available as validated method The LC-MSMS 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
4 Testicular size
Study design This is a multicentre longitudinal interventional randomized open-label phase III 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
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 fulfil 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 fulfil 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-MSMS Progesterone17-hydroxyprogesterone androstenedione didehydroepiandrosterone DHEA DHEA sulphate DHEAS corticosterone 11-deoxycortisol and cortisol using LC-MSMS 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
Each group will undergo two consecutive phases
1 Treatment phase
2 Follow-up phase The first phase will last two months and follow-up two months characterized by treatment withdrawal Total study duration is three months Patients will be evaluated two times weekly during the treatment phase and one time every two weeks during the follow-up phase The patient will be monitored for the safety at each visit by the medical staff at PI and participating centres The patient will remain under supervision for four hours at each visit
At each visit two blood samples will be collected Total of 18ml in the morning after an overnight fast The first serum sample will be stored at -20C and sent at the end of the study to Unit 1 for central measurements The second blood sample will be used locally to monitor the treatment efficacy and safety Overall the study protocol includes a screening visit followed by 18 visits During the study protocol pharmacovigilance will be performed according to Italian rules
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 1Total testosterone serum levels using LC-MSMS Other sex steroids using LC-MSMS Other hormonal analyses Biochemical evaluations performed at each centre 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 treatment phase V16 and at the end of follow-up phase scrotal ultrasound will be repeated to address possible morphological changes related to 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 nmolL the drug dosage will be not increased in both groups The hormonal results will be available in about 8 hours
Intervention The IMP is Luveris The comparator is Gonasi HP Luveris will be provided by Merck Gonasi HP will be purchased packages with vials of 250 1000 and 2000 IU each by the coordinating centre The entire amount of the IMP and comparator will be delivered to the pharmacy of the coordinating centre according to existing regulations and distributed in batches to the centres At the coordinating centre packages containing the number of ampoules sufficient for the patients to be allocated to the study within the next 6 months will be prepared and shipped to each centre The pharmacy of the coordinating centre will be responsible for IMP and comparator reception labelling packaging and sending to the centres according to existing regulations All medications to be used in this study will have been manufactured tested and released according to current GMP guidelines
The investigator or authorized staff will have to document the receipt dispensation and return of all IMPs received during this study Records on receipt use return loss or other disposition of IMPs will be maintained This process will be monitored by a CRO Clinical Research Organization during the study The IMP shipment will be provided in two times during the study duration
All remaining IMPs used and unused shall be collected and returned for destruction at the end of the study
Luveris will be self-administered once daily by the patient sc in the abdominal skin Patients will be properly trained on how to perform injection and reconstitute the product Since the sc route is generally preferred by patients this route is selected for this trial in order to increase treatment compliance Luveris will be package in vial of 75IU and it will be dissolved in a vial of solvent When higher dosages of Luveris will be needed for the protocol 150 300 and 600 2 4 and 8 vials of Luveris will be respectively dissolved in a single vial of solvent In particular when 300 IU should be used 4 Luveris vials will be dissolved in 2 vials of solvents When 600 IU should be used 8 Luveris vials will be dissolved in 3 vials of solvents
Gonasi HP will be injected im
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 are 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 IRBIEC will take place before 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 to the study will continue to receive their standard substitution therapy inasmuch needed thyroxine hydrocortisone During the study duration androgen replacement therapies will be not permitted
Luveris is provided in vials containing 75 IU of lyophilized material ampoules of solvent Patients in the study group will be instructed to use one viald during the first two weeks of treatment then two in the second two weeks four in the third two weeks and eight in the last two weeks of the treatment phase Up to 3 vials of lyophilized Luveris can be dissolved using only one vial of solvent whereas 4 Luveris vials will be dissolved in 2 solvents Eight Luveris vials will be dissolved in 3 solvents This will reduce discomfort for the patient Both IMP and comparator can be either self-administered by the patient or by a third person as described in the drug instructions At each visit empty vials will be collected by each centre to ensure patients compliance
All patients will be followed up for further 8 weeks after drug withdrawal according to the study design
Both LH and hCG are not known to interfere with other medications so that no specific drug including rescue medications is not allowed during the trial
Compliance will be monitored by asking the patients to return the empty Luveris and Gonasi HP ampoules and packages at the next visit In addition LHhCG and total testosterone serum levels will be measured at each visit before the next LHhCG injection at each participating centre
The study has a prospective interventional design Thus consecutive patients attending the participating Units will be enrolled according to inclusion and exclusion criteria 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 Thus the study design includes the randomization of eligible patients in study and control groups treated with Luveris and Gonasi HP respectively Patients allocation will follow the random sequence generated at Unit 1 before the start of the study The list will be generated using permuted blocks considering at maximum 10 patients for each Unit The randomization list will be sent to each Unit before study start Moreover being a pharmacodynamics phase II clinical trial a placebo-group is not foreseen The study however includes a group receiving the standard comparator in order to reveal possible qualitative differences eg serum steroid profile in the biological response in the male Considering the different frequency and route of drug administration in the two groups a double-blind design is not possible Indeed the study is open-label since each patient is aware of the LH or hCG dosage to be used Similarly clinicians involved in the study will be not blinded to allocation The following study personnel will be kept blinded to the treatment
The central lab in which LC-MSMS assays will be performed The clinician involved in scrotal ultrasound evaluations The statistician who finally will perform the statistical analysis
There are 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 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 investigators previous experience LH was administered as 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 1125 IU resulted in maximum testosterone levels of 485114 ngdl in the physiological range Similarly in the investigators 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
Data will be gathered with the following modalities
1 At the participating Units
1 patients clinical information including safety and tolerability as determined by AE SAE reporting vital signs ECG Concomitant medication laboratory parameters should be included in each panel eg for haematology chemistry urinalysis and evaluation of anti-Human-LH Antibodies formation in the serum
2 basal hormonal assessment
3 collection and storage of 2 serum samples 18 ml at -20
4 packaging and shipment of the samples to the centralized laboratory site Each Unit will receive from the Unit 1 a detailed investigator manual and a study kit containing tubes labels and boxes for sample storage and shipment All modalities of data collection will be explained in an investigator meeting before starting the study
Each participating Unit will follow and treat patients during the entire duration of the trial according to the study design and patients allocation All Units possess an institutional accreditation and have a quality management in place
2 At Unit 1 Coordinating centre
1 patients clinical information including safety and tolerability as determined by AE SAE reporting vital signs ECG Concomitant medication laboratory parameters should be included in each panel eg for haematology chemistry urinalysis and evaluation of anti-Human-LH Antibodies formation in the serum
2 basal hormonal assessment
3 collection and storage of 2 serum samples 18 ml at -20
4 At the end of the study the centre will receive all stored serum samples from the Units and provide centralized hormone analysis through LC-MSMS In addition all other parameters indicated in the section outcomes will be measured in the hormone laboratory using validated techniques
5 keep the overall database
6 perform data analysis All clinical and hormonal data will be recorded in appropriate electronic case report forms eCRFs provided by an experienced CRO These data together with hormonal parameters assessed centrally and eCRFs data will represent the dataset for the final analysis The quality of the data will be checked by monitoring site visits by an independent party the selected CRO
Follow up of the patients will last 2 months after drug withdrawal to check for return of the values to baseline The investigators planned a possible loss-to-follow-up of 10
Secondary end points
1 Full Safety profile see below the appropriate paragraph
2 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 eg in terms of serum testosterone increase per IU of r-hLH This parameter will be useful for future clinical studies based on LH
3 Comparison of steroid profiles hormone related profiles and serum levels of testicular steroids upon stimulation by LH or hCG by immunoassay and by LC-MSMS technique when available as validated method The LC-MSMS 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
4 Testicular size
Study design This is a multicentre longitudinal interventional randomized open-label phase III 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
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 fulfil 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 fulfil 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-MSMS Progesterone17-hydroxyprogesterone androstenedione didehydroepiandrosterone DHEA DHEA sulphate DHEAS corticosterone 11-deoxycortisol and cortisol using LC-MSMS 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
Each group will undergo two consecutive phases
1 Treatment phase
2 Follow-up phase The first phase will last two months and follow-up two months characterized by treatment withdrawal Total study duration is three months Patients will be evaluated two times weekly during the treatment phase and one time every two weeks during the follow-up phase The patient will be monitored for the safety at each visit by the medical staff at PI and participating centres The patient will remain under supervision for four hours at each visit
At each visit two blood samples will be collected Total of 18ml in the morning after an overnight fast The first serum sample will be stored at -20C and sent at the end of the study to Unit 1 for central measurements The second blood sample will be used locally to monitor the treatment efficacy and safety Overall the study protocol includes a screening visit followed by 18 visits During the study protocol pharmacovigilance will be performed according to Italian rules
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 1Total testosterone serum levels using LC-MSMS Other sex steroids using LC-MSMS Other hormonal analyses Biochemical evaluations performed at each centre 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 treatment phase V16 and at the end of follow-up phase scrotal ultrasound will be repeated to address possible morphological changes related to 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 nmolL the drug dosage will be not increased in both groups The hormonal results will be available in about 8 hours
Intervention The IMP is Luveris The comparator is Gonasi HP Luveris will be provided by Merck Gonasi HP will be purchased packages with vials of 250 1000 and 2000 IU each by the coordinating centre The entire amount of the IMP and comparator will be delivered to the pharmacy of the coordinating centre according to existing regulations and distributed in batches to the centres At the coordinating centre packages containing the number of ampoules sufficient for the patients to be allocated to the study within the next 6 months will be prepared and shipped to each centre The pharmacy of the coordinating centre will be responsible for IMP and comparator reception labelling packaging and sending to the centres according to existing regulations All medications to be used in this study will have been manufactured tested and released according to current GMP guidelines
The investigator or authorized staff will have to document the receipt dispensation and return of all IMPs received during this study Records on receipt use return loss or other disposition of IMPs will be maintained This process will be monitored by a CRO Clinical Research Organization during the study The IMP shipment will be provided in two times during the study duration
All remaining IMPs used and unused shall be collected and returned for destruction at the end of the study
Luveris will be self-administered once daily by the patient sc in the abdominal skin Patients will be properly trained on how to perform injection and reconstitute the product Since the sc route is generally preferred by patients this route is selected for this trial in order to increase treatment compliance Luveris will be package in vial of 75IU and it will be dissolved in a vial of solvent When higher dosages of Luveris will be needed for the protocol 150 300 and 600 2 4 and 8 vials of Luveris will be respectively dissolved in a single vial of solvent In particular when 300 IU should be used 4 Luveris vials will be dissolved in 2 vials of solvents When 600 IU should be used 8 Luveris vials will be dissolved in 3 vials of solvents
Gonasi HP will be injected im
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 are 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 IRBIEC will take place before 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 to the study will continue to receive their standard substitution therapy inasmuch needed thyroxine hydrocortisone During the study duration androgen replacement therapies will be not permitted
Luveris is provided in vials containing 75 IU of lyophilized material ampoules of solvent Patients in the study group will be instructed to use one viald during the first two weeks of treatment then two in the second two weeks four in the third two weeks and eight in the last two weeks of the treatment phase Up to 3 vials of lyophilized Luveris can be dissolved using only one vial of solvent whereas 4 Luveris vials will be dissolved in 2 solvents Eight Luveris vials will be dissolved in 3 solvents This will reduce discomfort for the patient Both IMP and comparator can be either self-administered by the patient or by a third person as described in the drug instructions At each visit empty vials will be collected by each centre to ensure patients compliance
All patients will be followed up for further 8 weeks after drug withdrawal according to the study design
Both LH and hCG are not known to interfere with other medications so that no specific drug including rescue medications is not allowed during the trial
Compliance will be monitored by asking the patients to return the empty Luveris and Gonasi HP ampoules and packages at the next visit In addition LHhCG and total testosterone serum levels will be measured at each visit before the next LHhCG injection at each participating centre
The study has a prospective interventional design Thus consecutive patients attending the participating Units will be enrolled according to inclusion and exclusion criteria 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 Thus the study design includes the randomization of eligible patients in study and control groups treated with Luveris and Gonasi HP respectively Patients allocation will follow the random sequence generated at Unit 1 before the start of the study The list will be generated using permuted blocks considering at maximum 10 patients for each Unit The randomization list will be sent to each Unit before study start Moreover being a pharmacodynamics phase II clinical trial a placebo-group is not foreseen The study however includes a group receiving the standard comparator in order to reveal possible qualitative differences eg serum steroid profile in the biological response in the male Considering the different frequency and route of drug administration in the two groups a double-blind design is not possible Indeed the study is open-label since each patient is aware of the LH or hCG dosage to be used Similarly clinicians involved in the study will be not blinded to allocation The following study personnel will be kept blinded to the treatment
The central lab in which LC-MSMS assays will be performed The clinician involved in scrotal ultrasound evaluations The statistician who finally will perform the statistical analysis
There are 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 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 investigators previous experience LH was administered as 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 1125 IU resulted in maximum testosterone levels of 485114 ngdl in the physiological range Similarly in the investigators 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
Data will be gathered with the following modalities
1 At the participating Units
1 patients clinical information including safety and tolerability as determined by AE SAE reporting vital signs ECG Concomitant medication laboratory parameters should be included in each panel eg for haematology chemistry urinalysis and evaluation of anti-Human-LH Antibodies formation in the serum
2 basal hormonal assessment
3 collection and storage of 2 serum samples 18 ml at -20
4 packaging and shipment of the samples to the centralized laboratory site Each Unit will receive from the Unit 1 a detailed investigator manual and a study kit containing tubes labels and boxes for sample storage and shipment All modalities of data collection will be explained in an investigator meeting before starting the study
Each participating Unit will follow and treat patients during the entire duration of the trial according to the study design and patients allocation All Units possess an institutional accreditation and have a quality management in place
2 At Unit 1 Coordinating centre
1 patients clinical information including safety and tolerability as determined by AE SAE reporting vital signs ECG Concomitant medication laboratory parameters should be included in each panel eg for haematology chemistry urinalysis and evaluation of anti-Human-LH Antibodies formation in the serum
2 basal hormonal assessment
3 collection and storage of 2 serum samples 18 ml at -20
4 At the end of the study the centre will receive all stored serum samples from the Units and provide centralized hormone analysis through LC-MSMS In addition all other parameters indicated in the section outcomes will be measured in the hormone laboratory using validated techniques
5 keep the overall database
6 perform data analysis All clinical and hormonal data will be recorded in appropriate electronic case report forms eCRFs provided by an experienced CRO These data together with hormonal parameters assessed centrally and eCRFs data will represent the dataset for the final analysis The quality of the data will be checked by monitoring site visits by an independent party the selected CRO
Follow up of the patients will last 2 months after drug withdrawal to check for return of the values to baseline The investigators planned a possible loss-to-follow-up of 10
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None