Trial Outcomes & Findings for Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency (NCT NCT02558829)

Last Updated: 2018-04-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

157 participants

Primary outcome timeframe

90 minutes

Results posted on

2018-04-10

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Group A Test Sequence MAC-ITT Group A: High likelihood of GHD: * structural hypothalamic or pituitary lesions and low 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. Randomization of GHST administration to following test sequence: 1st Macimorelin-GHST (MAC), 2nd Insulin Tolerance Test (ITT). Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose. Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose.	Group A Test Sequence ITT-MAC Group A: High likelihood of GHD: * structural hypothalamic or pituitary lesions and low 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 Randomization of GHST administration to following test sequence: 1st Insulin Tolerance Test (ITT), 2nd Macimorelin-GHST (MAC) Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose. Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose.	Group B Test Sequence MAC-ITT Group B: intermediate likelihood of GHD: \- eligible subjects not qualifying for either high or low likelihood (Group A/C) Randomization of GHST administration to following test sequence: 1st Macimorelin-GHST (MAC), 2nd Insulin Tolerance Test (ITT). Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose. Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose.	Group B Test Sequence ITT- MAC Group B: intermediate likelihood of GHD: \- eligible subjects not qualifying for either high or low likelihood (Group A/C) Randomization of GHST administration to following test sequence: 1st Insulin Tolerance Test (ITT), 2nd Macimorelin-GHST (MAC) Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose. Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose.	Group C Test Sequence MAC-ITT 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. Randomization of GHST administration to following test sequence: 1st Macimorelin-GHST (MAC), 2nd Insulin Tolerance Test (ITT). Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose. Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose.	Group C Test Sequence ITT-MAC 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. Randomization of GHST administration to following test sequence: 1st Insulin Tolerance Test (ITT), 2nd Macimorelin-GHST (MAC) Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose. Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose.	Group D Test Sequence MAC-ITT Group D: Healthy control. Healthy subjects matching Group A subjects by sex, age, BMI, and estrogen status (females only). Randomization of GHST administration to following test sequence: 1st Macimorelin-GHST (MAC), 2nd Insulin Tolerance Test (ITT). Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose. Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose.	Group D Test Sequence ITT-MAC Group D: Healthy control. Healthy subjects matching Group A subjects by sex, age, BMI, and estrogen status (females only). Randomization of GHST administration to following test sequence: 1st Insulin Tolerance Test (ITT), 2nd Macimorelin-GHST (MAC) Insulin Tolerance Test: administration of regular human insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose. Macimorelin GHST: administration of macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose.
Overall Study STARTED	21	21	24	18	18	26	18	11
Overall Study COMPLETED	20	18	21	16	16	24	17	8
Overall Study NOT COMPLETED	1	3	3	2	2	2	1	3

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group A n=42 Participants 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.	Group B n=42 Participants Intermediate likelihood of GHD: • Eligible subjects not qualifying for either high or low likelihood (Group A/C)	Group C n=44 Participants 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	Group D n=29 Participants Healthy control. Healthy subjects matching Group A subjects by sex, age, body mass index (BMI), and estrogen status (females only).	Total n=157 Participants Total of all reporting groups
Age, Continuous	42.3 years STANDARD_DEVIATION 15.0 • n=5 Participants	45.8 years STANDARD_DEVIATION 11.8 • n=7 Participants	34.9 years STANDARD_DEVIATION 10.5 • n=5 Participants	40.0 years STANDARD_DEVIATION 12.4 • n=4 Participants	40.7 years STANDARD_DEVIATION 13.1 • n=21 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	24 Participants n=7 Participants	9 Participants n=5 Participants	14 Participants n=4 Participants	64 Participants n=21 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	18 Participants n=7 Participants	35 Participants n=5 Participants	15 Participants n=4 Participants	93 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	9 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	15 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	34 Participants n=5 Participants	29 Participants n=7 Participants	36 Participants n=5 Participants	29 Participants n=4 Participants	128 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	0 Participants n=4 Participants	14 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) White	36 Participants n=5 Participants	36 Participants n=7 Participants	34 Participants n=5 Participants	29 Participants n=4 Participants	135 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	0 Participants n=4 Participants	13 Participants n=21 Participants
Region of Enrollment Austria	4 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	7 Participants n=21 Participants
Region of Enrollment United States	6 Participants n=5 Participants	13 Participants n=7 Participants	18 Participants n=5 Participants	0 Participants n=4 Participants	37 Participants n=21 Participants
Region of Enrollment Poland	2 Participants n=5 Participants	4 Participants n=7 Participants	14 Participants n=5 Participants	29 Participants n=4 Participants	49 Participants n=21 Participants
Region of Enrollment United Kingdom	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment Italy	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment France	3 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	12 Participants n=21 Participants
Region of Enrollment Serbia	12 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	0 Participants n=4 Participants	21 Participants n=21 Participants
Region of Enrollment Germany	8 Participants n=5 Participants	12 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	21 Participants n=21 Participants
Region of Enrollment Spain	7 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	8 Participants n=21 Participants
Body Mass Index (kg/m^2)	27.6 kg/m^2 STANDARD_DEVIATION 4.6 • n=5 Participants	29.8 kg/m^2 STANDARD_DEVIATION 4.5 • n=7 Participants	27.9 kg/m^2 STANDARD_DEVIATION 5.7 • n=5 Participants	26.1 kg/m^2 STANDARD_DEVIATION 3.2 • n=4 Participants	28.0 kg/m^2 STANDARD_DEVIATION 4.8 • n=21 Participants

PRIMARY outcome

Timeframe: 90 minutes

Population: All subjects from Groups A, B, C, D included in the modified intention-to-treat (mITT) analysis, N=140

Outcome measures

Outcome measures
Measure	Positive MAC, Positive ITT n=140 Participants Test outcome positive for MAC and for ITT	Positive MAC, Negative ITT n=140 Participants Test outcome positive for MAC and negative for ITT	Negative MAC, Positive ITT n=140 Participants Test outcome negative for MAC and positive for ITT	Negative MAC, Negative ITT n=140 Participants Test outcome negative for MAC and for ITT
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT	55 Participants	4 Participants	19 Participants	62 Participants

SECONDARY outcome

Timeframe: 90 minutes

Population: All subjects from Groups A, B, C, D included in the modified intention-to-treat (mITT) analysis, N=140

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.

Outcome measures

Outcome measures
Measure	Positive MAC, Positive ITT n=140 Participants Test outcome positive for MAC and for ITT	Positive MAC, Negative ITT n=140 Participants Test outcome positive for MAC and negative for ITT	Negative MAC, Positive ITT n=140 Participants Test outcome negative for MAC and positive for ITT	Negative MAC, Negative ITT n=140 Participants Test outcome negative for MAC and for ITT
Overall Agreements (Positive/ Negative) for MAC and ITT	55 Participants	4 Participants	19 Participants	62 Participants

SECONDARY outcome

Timeframe: up to 70 days

Population: All subjects of Group A, B, C, D in the safety population.

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.

Outcome measures

Outcome measures
Measure	Positive MAC, Positive ITT n=157 Participants Test outcome positive for MAC and for ITT	Positive MAC, Negative ITT n=154 Participants Test outcome positive for MAC and negative for ITT	Negative MAC, Positive ITT Test outcome negative for MAC and positive for ITT	Negative MAC, Negative ITT Test outcome negative for MAC and for 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	39 Participants	—	—
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	22 Participants	—	—
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	1 Participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Positive MAC, Positive ITT n=153 Participants Test outcome positive for MAC and for ITT	Positive MAC, Negative ITT n=153 Participants Test outcome positive for MAC and negative for ITT	Negative MAC, Positive ITT n=156 Participants Test outcome negative for MAC and positive for ITT	Negative MAC, Negative ITT n=155 Participants Test outcome negative for MAC and for ITT
ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose	63.4 beats per minute Standard Deviation 10.35	60.5 beats per minute Standard Deviation 9.47	63.7 beats per minute Standard Deviation 10.70	65.6 beats per minute Standard Deviation 10.90

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Exploratory evaluation of sensitivity and specificity of the MAC as performance characteristic, based on test outcome in Group A and Group D subjects.

Outcome measures

Outcome measures
Measure	Positive MAC, Positive ITT n=38 Participants Test outcome positive for MAC and for ITT	Positive MAC, Negative ITT n=25 Participants Test outcome positive for MAC and negative for ITT	Negative MAC, Positive ITT n=38 Participants Test outcome negative for MAC and positive for ITT	Negative MAC, Negative ITT n=25 Participants Test outcome negative for MAC and for ITT
Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL	33 Participants	1 Participants	5 Participants	24 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	Positive MAC, Positive ITT n=34 Participants Test outcome positive for MAC and for ITT	Positive MAC, Negative ITT n=34 Participants Test outcome positive for MAC and negative for ITT	Negative MAC, Positive ITT n=34 Participants Test outcome negative for MAC and positive for ITT	Negative MAC, Negative ITT n=34 Participants Test outcome negative for MAC and for ITT
Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)	16 Participants	2 Participants	16 Participants	0 Participants

Adverse Events

Macimorelin GHST (MAC), SAF Population

Serious events: 1 serious events

Other events: 39 other events

Deaths: 0 deaths

Insulin Tolerance Test (ITT), SAF Population

Serious events: 1 serious events

Other events: 151 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Macimorelin GHST (MAC), SAF Population n=154 participants at risk Macimorelin GHST (MAC): combined safety data from core study and repeatability extension (Amendment 1, European sites only)). All subjects of Group A, B, C, D with at least one macimorelin GHST performed: N=154. All subjects of Group A, B, C, D valid for safety (SAF) analysis: N=157. (three subjects were exposed to the ITT only). Repeatability extension (planned repetition of the MAC): subjects of Group A, B, C valid for safety (SAF)analysis: N=34.	Insulin Tolerance Test (ITT), SAF Population n=157 participants at risk Insulin Tolerance Test (ITT) All subjects of Group A, B, C, D with at least one ITT performed: N=157. All subjects of Group A, B, C, D valid for safety (SAF) analysis: N=157.
Injury, poisoning and procedural complications Upper limp fracture	0.65% 1/154 • Number of events 1 • Throughout the trial, i.e. over a period of ca. 15 months, the subjects were questioned and/or examined by the Investigators or his/her designee for evidence of adverse events (AEs). Per subject, the time frame for collection of such data was up to 70 days. GHST emergent adverse events (TEAEs): all untoward effects during or after a GHST were documented in the electronic Case Report Form (eCRF), to ensure balanced representation of both GHSTs. Safety analyses were conducted using data from the Safety Population (SAF). The number and percentage of subjects with TEAEs was displayed for each GHST test drug by SOC and preferred term. Additionally, TEAEs were tabulated for each GHST by severity and by relationship to the GHST test drug.	0.64% 1/157 • Number of events 1 • Throughout the trial, i.e. over a period of ca. 15 months, the subjects were questioned and/or examined by the Investigators or his/her designee for evidence of adverse events (AEs). Per subject, the time frame for collection of such data was up to 70 days. GHST emergent adverse events (TEAEs): all untoward effects during or after a GHST were documented in the electronic Case Report Form (eCRF), to ensure balanced representation of both GHSTs. Safety analyses were conducted using data from the Safety Population (SAF). The number and percentage of subjects with TEAEs was displayed for each GHST test drug by SOC and preferred term. Additionally, TEAEs were tabulated for each GHST by severity and by relationship to the GHST test drug.

Other adverse events

Additional Information

Dr. Nicola Ammer

Aeterna Zentaris

Phone: +496942602

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee INSTITUTIONS / INVESTIGATORS are allowed to publish data pursuant to the Sponsor's publication policies per individual agreements. Any material prepared for publication shall be submitted to the Sponsor for review and comment within an individually agreed period (30 up to 180 days). INSTITUTION / INVESTIGATOR shall modify the publication / presentation according to the comments by the Sponsor, provided that the scientific neutrality of the publication is not impaired hereby.
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Restriction type: OTHER