Growth Hormone Deficiency With Pituitary Anomalies
Conditions
Keywords
Adult Growth Hormone Deficiency
Brief summary
The Macimorelin Growth Hormone Stimulation Test (GHST) will be compared with the Insulin Tolerance Test (ITT) in an open-label, randomized, 2-way crossover Trial. The trial will include subjects suspected to have adult growth hormone deficiency (AGHD) and a group of healthy control subjects.
Detailed description
Trial subjects will be assigned to groups of descending likelihood of having AGHD: Group A, B, C: High, intermediate, and low likelihood of GHD, respectively; Group D: Healthy control subjects matching Group A subjects . The sequential order of the GHSTs for suspected AGHD subjects (Group A-C) will be determined by stratified randomization; healthy control subjects (Group D) will be tested in the same sequence as the matched Group A subjects. Serum concentrations of GH will be measured at pre-defined time points before and after GHST with macimorelin or insulin. A peak GH value below the GHST-specific cut-off value will be considered 'test positive'. The ITT will be considered as comparator (non-reference standard) to assess positive and negative agreement of both GHSTs, based on the predefined cut-off values. The following cut-off values for simulated GH levels were used for both GHST tests to be compared: macimorelin-GHST: GH: 2.8 ng/mL, ITT: GH: 5.1 ng/mL. Amendment no. 1 (repeatability extension): had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects (planned N=30, 10 per Group) that had completed the core study.
Interventions
DRUGMacimorelin
macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose
DRUGInsulin
Insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose
Sponsors
AEterna Zentaris
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
Masking description
This was an open label trial. No masking with regard to the Growth Hormone Stimulation Tests (GHSTs) performed was done. However, Data Review Committee/Sponsor/Project Management was masked towards the Growth Hormone (GH) values as results fo both tests. GH values were provided to the investigator only after both GHSTs had been performed, to avoid bias.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Suspected growth hormone deficiency (GHD), based on either of the following: * structural hypothalamic or pituitary disease, or * surgery or irradiation in these areas, or * head trauma as an adult, or * evidence of other pituitary hormone deficiencies, or * idiopathic childhood onset GHD (without known hypothalamic or pituitary lesion or injury). * Healthy\* control subjects, matching a 'high likelihood GHD' subjects
Exclusion criteria
* GH therapy within 1 month prior to anticipated first GHST within this trial (within 3 months in case of long-acting GH formulation). * GHST within 7 days prior to the anticipated first test day within the trial. * Subjects with a medical history and clinical signs of a not adequately treated thyroid dysfunction or subjects who had a change in thyroid therapy within 30 days prior to anticipated first test day within the trial. * Untreated hypogonadism or not on a stable substitution treatment within 30 days prior to anticipated first test day within the trial. * Treatment with drugs directly affecting the pituitary secretion of somatotropin (e.g. somatostatin analogues, clonidine, levodopa, and dopamine agonists) or provoking the release of somatostatin; antimuscarinic agents (atropine). * Concomitant use of a CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort). * Medical history of ongoing clinically symptomatic severe psychiatric disorders. * Parkinson's disease. * Cushing disease or patients on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated first test day within the trial. * Type 1 diabetes or untreated or poorly controlled Type 2 diabetes, as defined by HbA1c \> 8%. * Body mass index (BMI) ≥ 40.0 kg/m2. * Participation in a trial with any investigational drug within 30 days prior to trial entry. * Vigorous physical exercise within 24 hours prior to each GHST within this trial. * Known hypersensitivity to macimorelin or insulin, or any of the constituents of either preparation. * Clinically significant cardiovascular or cerebrovascular disease. * Prolonged ECG QT interval, defined as corrected QT interval (QTc) \> 500 msec. * Concomitant treatment with any drugs that might prolong QT/QTc. * Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (aspartate amino transferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transpeptidase (GGT)\> 2.5 x ULN; ), creatinine, or bilirubin \> 1.5x ULN). * Medical history of seizure disorders. * Known immunosuppression. * Current active malignancy other than non-melanoma skin cancer. * Breastfeeding or positive urine pregnancy test (for women of childbearing potential only). * Women of childbearing age without contraception, such as hormonal contraception or use of condom and spermicides or use of diaphragm and spermicides or Intra Uterine Device (IUD). * Lack of ability or willingness to give informed consent. * Anticipated non-availability for trial visits/procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT | 90 minutes | In the primary efficacy analysis, the estimated percentages of the agreements and the two-sided 95% confidence interval (or one-sided 97.5% confidence interval) of the percent agreement based on Clopper-Pearson are presented. The probability for a Negative Agreement equals the sum of the probability of both tests being correct (negative test results for both tests for subjects with true non-AGHD) and the probability of both tests being wrong (negative test results for both tests for subjects with true AGHD). The performance of the GHST with Macimorelin was considered to be acceptable if the lower bound of the two-sided 95% confidence interval (or lower bound of the one-sided 97.5% confidence interval) for the primary efficacy variables was 75% or higher for 'percent negative agreement', and 70% or higher for the 'percent positive agreement'. The following cut-off values for stimulated GH levels were used: - MAC: GH: 2.8 ng/mL, - ITT: GH: 5.1 ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Agreements (Positive/ Negative) for MAC and ITT | 90 minutes | As part of the secondary efficacy analysis, the percent of overall agreement was analyzed, using the same methodology described for the analyses for the primary efficacy variables. |
| Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | up to 70 days | GHST ('Test') emergent AEs (TEAEs): AEs occurring or observed from the day of first GHST (administration of an IMP) throughout End-of-Study (EOS) visit or Early Termination, whichever occurred first. TEAEs were analyzed and compared for both GHSTs. Detailed listings are presented in the Adverse Events section. The frequencies presented in this section refer to number of subjects with any TEAE, each subject was counted only once within each category. |
| ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose | 60 minutes | During the GHSTs, ECGs were measured at pre-dose (up to 15 min before) and 60 minutes post-dose. Furthermore, ECGs were measured at screening and at End-of-Study (EOS) Visit. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL | 90 minutes | Exploratory evaluation of sensitivity and specificity of the MAC as performance characteristic, based on test outcome in Group A and Group D subjects. |
| Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1) | 90 minutes | Amendment no 1 (repeatability extension) had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Agreements were calculated with two-sided 95% confidence intervals. |
Countries
Austria, France, Germany, Italy, Poland, Serbia, Spain, United Kingdom, United States
Participant flow
Recruitment details
Study centers: 30 sites in 9 countries had been initiated,i.e. 25 sites in Europe (Austria, Germany, Spain, France, Italy, Poland, Serbia, and UK) with 21 of them becoming active, and 5 sites in the USA. Study period: first subject screened: 01-Oct-2015, first subject randomized (= enrolled): 03-Dec-2015, Last subject completed: 29-Nov-2016.
Pre-assignment details
A subject registered in the eCRF as 'eligible' was assigned to the applicable Group A/B/C (= stratum). The sequence for performance of both growth hormone stimulation tests (GHSTs) in Group A/B/C subjects was assigned by stratified randomization. Healthy control subjects (Group D) were tested in the same sequence as the matched Group A subjects.
Participants by arm
| Arm | Count |
|---|---|
| Group A High likelihood of growth hormone deficiency (GHD):
* Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or
* Three or more pituitary hormone deficiencies (PHD) and low IGF-1, or
* Childhood onset GHD with structural lesions and low IGF-1. | 42 |
| Group B Intermediate likelihood of GHD:
• Eligible subjects not qualifying for either high or low likelihood (Group A/C) | 42 |
| Group C Low likelihood of GHD:
* One risk factor for GHD only, such as history of distant traumatic brain injury (TBI) or one PHD only with otherwise normal pituitary function or
* Isolated idiopathic childhood onset GHD without additional pituitary deficits | 44 |
| Group D Healthy control. Healthy subjects matching Group A subjects by sex, age, body mass index (BMI), and estrogen status (females only). | 29 |
| Total | 157 |
Baseline characteristics
| Characteristic | Group B | Group C | Group D | Group A | Total |
|---|---|---|---|---|---|
| Age, Continuous | 45.8 years STANDARD_DEVIATION 11.8 | 34.9 years STANDARD_DEVIATION 10.5 | 40.0 years STANDARD_DEVIATION 12.4 | 42.3 years STANDARD_DEVIATION 15 | 40.7 years STANDARD_DEVIATION 13.1 |
| Body Mass Index (kg/m^2) | 29.8 kg/m^2 STANDARD_DEVIATION 4.5 | 27.9 kg/m^2 STANDARD_DEVIATION 5.7 | 26.1 kg/m^2 STANDARD_DEVIATION 3.2 | 27.6 kg/m^2 STANDARD_DEVIATION 4.6 | 28.0 kg/m^2 STANDARD_DEVIATION 4.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 2 Participants | 0 Participants | 4 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 36 Participants | 29 Participants | 34 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 0 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 0 Participants | 4 Participants | 13 Participants |
| Race (NIH/OMB) White | 36 Participants | 34 Participants | 29 Participants | 36 Participants | 135 Participants |
| Region of Enrollment Austria | 3 Participants | 0 Participants | 0 Participants | 4 Participants | 7 Participants |
| Region of Enrollment France | 5 Participants | 4 Participants | 0 Participants | 3 Participants | 12 Participants |
| Region of Enrollment Germany | 12 Participants | 1 Participants | 0 Participants | 8 Participants | 21 Participants |
| Region of Enrollment Italy | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Poland | 4 Participants | 14 Participants | 29 Participants | 2 Participants | 49 Participants |
| Region of Enrollment Serbia | 2 Participants | 7 Participants | 0 Participants | 12 Participants | 21 Participants |
| Region of Enrollment Spain | 1 Participants | 0 Participants | 0 Participants | 7 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 13 Participants | 18 Participants | 0 Participants | 6 Participants | 37 Participants |
| Sex: Female, Male Female | 24 Participants | 9 Participants | 14 Participants | 17 Participants | 64 Participants |
| Sex: Female, Male Male | 18 Participants | 35 Participants | 15 Participants | 25 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 154 | 0 / 157 |
| other Total, other adverse events | 39 / 154 | 151 / 157 |
| serious Total, serious adverse events | 1 / 154 | 1 / 157 |
Outcome results
Primary
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT
In the primary efficacy analysis, the estimated percentages of the agreements and the two-sided 95% confidence interval (or one-sided 97.5% confidence interval) of the percent agreement based on Clopper-Pearson are presented. The probability for a Negative Agreement equals the sum of the probability of both tests being correct (negative test results for both tests for subjects with true non-AGHD) and the probability of both tests being wrong (negative test results for both tests for subjects with true AGHD). The performance of the GHST with Macimorelin was considered to be acceptable if the lower bound of the two-sided 95% confidence interval (or lower bound of the one-sided 97.5% confidence interval) for the primary efficacy variables was 75% or higher for 'percent negative agreement', and 70% or higher for the 'percent positive agreement'. The following cut-off values for stimulated GH levels were used: - MAC: GH: 2.8 ng/mL, - ITT: GH: 5.1 ng/mL.
Time frame: 90 minutes
Population: All subjects from Groups A, B, C, D included in the modified intention-to-treat (mITT) analysis, N=140
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Positive MAC, Positive ITT | Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT | 55 Participants |
| Positive MAC, Negative ITT | Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT | 4 Participants |
| Negative MAC, Positive ITT | Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT | 19 Participants |
| Negative MAC, Negative ITT | Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT | 62 Participants |
Comparison: The estimated percentages of the agreements and the two-sided 95% confidence interval (or one-sided 97.5% confidence interval) of the percent agreement based on Clopper-Pearson are presented. The performance of the MAC (cut-off point 2.8 ng/mL) was considered to be acceptable if the lower bound of the two-sided 95% CI (or lower bound of the one-sided 97.5% CI) was 75% or higher for 'percent negative agreement', and 70% or higher for the 'percent positive agreement'.95% CI: [62.84, 83.78]
Comparison: Please refer to Statistical Analysis 1.95% CI: [85.2, 98.32]
Secondary
ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose
During the GHSTs, ECGs were measured at pre-dose (up to 15 min before) and 60 minutes post-dose. Furthermore, ECGs were measured at screening and at End-of-Study (EOS) Visit.
Time frame: 60 minutes
Population: All subjects of Group A, B, C, D in the safety population. Because of single ECGs missing, the number of participants analyzed here is lower than the number of the subjects in the SAF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive MAC, Positive ITT | ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose | 63.4 beats per minute | Standard Deviation 10.35 |
| Positive MAC, Negative ITT | ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose | 60.5 beats per minute | Standard Deviation 9.47 |
| Negative MAC, Positive ITT | ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose | 63.7 beats per minute | Standard Deviation 10.7 |
| Negative MAC, Negative ITT | ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose | 65.6 beats per minute | Standard Deviation 10.9 |
Comparison: Pre/post dose comparison of ECGs was done for both GHSTs. During the GHSTs, ECGs were measured at pre-dose (up to 15 min before) and 60 minutes post-dose. Furthermore, ECGs were measured at screening and at End-of-Study (EOS) Visit.~Calculations were done from two time points: baseline and 60 min post-dose. Baseline is either the screening or pre-dose value.
Secondary
Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE
GHST ('Test') emergent AEs (TEAEs): AEs occurring or observed from the day of first GHST (administration of an IMP) throughout End-of-Study (EOS) visit or Early Termination, whichever occurred first. TEAEs were analyzed and compared for both GHSTs. Detailed listings are presented in the Adverse Events section. The frequencies presented in this section refer to number of subjects with any TEAE, each subject was counted only once within each category.
Time frame: up to 70 days
Population: All subjects of Group A, B, C, D in the safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Positive MAC, Positive ITT | Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | Any TEAE (any relation) | 151 Participants |
| Positive MAC, Positive ITT | Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | Any TEAE (likely or possible related) | 149 Participants |
| Positive MAC, Positive ITT | Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | Any test emergent severe AE | 11 Participants |
| Positive MAC, Negative ITT | Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | Any TEAE (any relation) | 39 Participants |
| Positive MAC, Negative ITT | Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | Any TEAE (likely or possible related) | 22 Participants |
| Positive MAC, Negative ITT | Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE | Any test emergent severe AE | 1 Participants |
Secondary
Overall Agreements (Positive/ Negative) for MAC and ITT
As part of the secondary efficacy analysis, the percent of overall agreement was analyzed, using the same methodology described for the analyses for the primary efficacy variables.
Time frame: 90 minutes
Population: All subjects from Groups A, B, C, D included in the modified intention-to-treat (mITT) analysis, N=140
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Positive MAC, Positive ITT | Overall Agreements (Positive/ Negative) for MAC and ITT | 55 Participants |
| Positive MAC, Negative ITT | Overall Agreements (Positive/ Negative) for MAC and ITT | 4 Participants |
| Negative MAC, Positive ITT | Overall Agreements (Positive/ Negative) for MAC and ITT | 19 Participants |
| Negative MAC, Negative ITT | Overall Agreements (Positive/ Negative) for MAC and ITT | 62 Participants |
Comparison: This variable was analyzed using the same methodology described for the analyses for the primary efficacy variables. in the below, the results for Step 1 (peak GH level among all post baseline samples) are presented.95% CI: [76.38, 89.29]
Other Pre-specified
Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)
Amendment no 1 (repeatability extension) had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Agreements were calculated with two-sided 95% confidence intervals.
Time frame: 90 minutes
Population: All subjects included in the modified intention-to-treat (mITT) analysis who also participated in the repeatability extension, i.e. N=34 (comprising 13 Group A, 12 Group B, and 9 Group C subjects).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Positive MAC, Positive ITT | Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1) | 16 Participants |
| Positive MAC, Negative ITT | Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1) | 2 Participants |
| Negative MAC, Positive ITT | Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1) | 16 Participants |
| Negative MAC, Negative ITT | Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1) | 0 Participants |
Comparison: Please refer to Statistical Analysis 1 for this outcome.95% CI: [65.29, 98.62]
Comparison: Amendment no 1 had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study.95% CI: [79.41, 100]
Other Pre-specified
Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL
Exploratory evaluation of sensitivity and specificity of the MAC as performance characteristic, based on test outcome in Group A and Group D subjects.
Time frame: 90 minutes
Population: All high likelihood AGHD subjects of Group A (N=38) of the mITT population as 'true' AGHD subjects and all healthy matching subjects of Group D (N=25) of the mITT population as 'true' AGHD negative subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Positive MAC, Positive ITT | Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL | 33 Participants |
| Positive MAC, Negative ITT | Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL | 1 Participants |
| Negative MAC, Positive ITT | Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL | 5 Participants |
| Negative MAC, Negative ITT | Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL | 24 Participants |
Comparison: Sensitivity was estimated for the MAC at the pre-defined cut-off point GH: 2.8 ng/mL.95% CI: [0.72, 0.96]
Comparison: Specificity was estimated for the MAC at the pre-defined cut-off point GH: 2.8 ng/mL.95% CI: [0.8, 1]