Macimorelin as a diagnostic test for AGHD 1 Macimorelin as a Diagnostic Test for Adult Growth Hormone Deficiency
2
3 Jose M Garcia MD PhD1*, Beverly MK Biller MD2, Márta Korbonits MD PhD3, Vera
4 Popovic MD PhD4, Anton Luger DrMed5, Christian J. Strasburger MD6, Philippe Chanson
5 MD7, Milica Medic-Stojanoska MD8, Jochen Schopohl MD9, Anna Zakrzewska MD PhD10,
6 Sandra Pekic-Djurdjevic MD11, Marek Bolanowski MD PhD12, Ronald Swerdloff MD13,
7 Christina Wang MD13, Thomas Blevins MD14, Marco Marcelli MD15, Nicola Ammer MD
8 PhD16, Richard Sachse MD PhD16, Kevin CJ Yuen MD17 on behalf of the Macimorelin for
9 AGHD Diagnosis Study Groupϕ.
10
11 1GRECC VA Puget Sound HCS/University of Washington, Seattle, WA, USA;
12 2Massachusetts General Hospital, Boston, MA; USA; 3Barts and the London School of
13 Medicine, Queen Mary University of London, London, UK; 4Medical Faculty, University of
14 Belgrade, Serbia; 5Medical University, General Hospital, Vienna, Austria; 6Charité-
15 Universitatsmedizin, Berlin, Germany; 7Assistance Publique-Hôpitaux de Paris, Hôpital de
16 Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence
17 des Maladies Rares de l’Hypophyse, Le Kremlin Bicêtre, F-94275, and UMS 1185, Fac Med
18 Paris Sud, Univ Paris-Sud, Le Kremlin-Bicêtre, F-94276, France; 8University of Novi Sad,
19 Faculty of Medicine, Clinical Center of Vojvodina, Novi Sad, Serbia; 9Medizinische Klinik
20 IV, LMU München, 10Angelius Provita Medical Center, Katowice, Poland; 11University
21 Clinical Center, Belgrade, Serbia; 12Wromedica, Medical University Wroclaw, Wrocław,
22 Poland; 13LA Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA; 14Texas
23 Diabetes and Endocrinology, Austin, TX, 15 Baylor Coll Med & Michael E. DeBakey VA
1
Macimorelin as a diagnostic test for AGHD 24 Medical Center, Houston, TX, USA; 16Aeterna Zentaris, Frankfurt, Germany; 17Swedish
25 Neuroscience Institute, Seattle, WA, USA.
26
27 *Corresponding author and person to whom reprint request should be addressed:
28 Jose M. Garcia, MD, PhD
29 Geriatric Research, Education and Clinical Center
30 VA Puget Sound Health Care System
31 University of Washington
32 1660 South Columbian Way (S-182-GRECC)
33 Seattle, WA 98108-1597
35 Phone: (206) 764-2984
36 Fax: (206) 764-2569
37
38 Macimorelin for AGHD Diagnosis Study Group:
39 Claire Higham D Phil MBBS: The Christie NHS Foundation Trust, Manchester, UK
40 Thomas Blevins MD: Texas Diabetes and Endocrinology, Austin, TX, USA
41 Marek Bolanowski MD PhD: Wromedica, Medical University Wroclaw, Wrocław, Poland
42 Françoise Borson Chazot MD: CHU de Lyon HCL-GH Est, Bron-Cedex, France
43 Philippe Chanson MD: APHP, GHU Paris-Sud - Hôpital de Bicêtre, Le Kremlin-Bicêtre,
44 France
45 Jose M. Garcia MD PhD: GRECC VA Puget Sound HCS/University of Washington, Seattle,
46 WA, USA
47 Bożena Górnikiewicz-Brzezicka MD: Centrum Kliniczno-Badawcze, Elblag, Poland 2
Macimorelin as a diagnostic test for AGHD 48 Peter Kann MD: University Hospital, Marburg, Germany
49 Wolfram Karges MD: RWTH Aachen University Hospital, Aachen, Germany
50 Márta Korbonits MD PhD: Barts and the London School of Medicine, Queen Mary
51 University, London, UK
52 Anton Luger Dr Med: Medical University, General Hospital, Vienna, Austria
53 Marco Marcelli MD: Baylor College of Medicine / Michael E. DeBakey VA Medical Center,
54 Houston, TX, USA
55 Milica Medic-Stojanoska MD: University of Novi Sad, Faculty of Medicine, Clinical Center
56 of Vojvodina, Novi Sad, Serbia
57 Gabriel Obiols MD: Hospital Universitari Vall d' Hebron, Barcelona, Spain
58 Sandra Pekic-Djurdjevic MD: Clinical Center, University of Belgrade, Serbia
59 Luca Persani MD: Department of Clinical Sciences and Community Health, University of
60 Milan, 20100 Milan, Italy; Division of Endocrine and Metabolic Diseases, Istituto Auxologico
61 Italiano, 20149 Milan, Italy
62 Christoph Schnack MD: Krankenanstalt Rudolfstiftung, Vienna, Austria
63 Jochen Schopohl MD: Medizinische Klinik IV, LMU München, Munich, Germany
64 Günter Stalla MD: Max Planck Institute, Munich, Germany
65 Christian Strasburger MD: Charité, Berlin, Germany
66 Ronald Swerdloff MD and Christina Wang MD: LA Biomedical Research Institute at Harbor-
67 UCLA; Torrance, CA, USA
68 Antoine Tabarin MD: Hôpital Haut-Lévêque, Pessac, France
69 Susan Webb MD: Hospital Sant Pau, Ciberer group 747, Universitat Autònoma de Barcelona,
70 Barcelona, Spain
71 Kevin Yuen MD: Swedish Neuroscience Institute, Seattle, WA, USA 3
Macimorelin as a diagnostic test for AGHD 72 Anna Zakrzewska MD PhD: Angelius Provita Medical Center, Katowice, Poland
73
74 Disclosure Summary and Conflicts of Interests: All authors received research support from
75 Aeterna Zentaris Inc. JMG receives research support from Pfizer Inc. BMKB has been the PI
76 of research grants to Massachusetts General Hospital from OPKO and Novo Nordisk and
77 consulted for Aeterna Zentaris, Ferring, Merck Serono, Novo Nordisk, OPKO, Sandoz and
78 Pfizer. MK consulted for Aeterna Zentaris, Ferring, ONO and Pfizer. PC has received
79 unrestricted research and educational grants from Ipsen, Novartis, Novo-Nordisk, and Pfizer
80 as Head of the Department of Endocrinology and Reproductive Diseases,
81 Hôpitaux Universitaires Paris-Sud ; he has served as PI for clinical trials funded by Novartis,
82 Pfizer, Ipsen, Italpharmaco, Antisense, Prolor Biotech; he is a member of Advisory Boards
83 from Ipsen, Novartis, Viropharma and has been a member of the Advisory Board of HypoCCS
84 sponsored by Eli Lilly; he gave lectures for Ipsen, Novartis, and Pfizer. All the fees and
85 honoraria are paid to his Institution. CJS consulted for Aeterna Zentaris, Chiasma, Pfizer,
86 Prolor, Merck Serono, Versartis, NovoNordisk and Sandoz. RSS is a consultant for Novartis,
87 Clarus and Antares and has received research support from Clarus Therapeutics. CW received
88 research support from Clarus Therapeutics. KCJY has been the PI of research grants to the
89 Swedish Neuroscience Institute from Pfizer, Novo Nordisk, Teva Pharmaceuticals, OPKO
90 Biologics, and Versartis, and consulted for Aeterna Zentaris, Pfizer, Novo Nordisk, Sandoz,
91 and Versartis.
92
93 Funding source: Aeterna Zentaris funded this study.
94
95 Keywords: ghrelin, diagnosis, insulin tolerance 4
Macimorelin as a diagnostic test for AGHD 96
97 ABSTRACT
98 PURPOSE: Diagnosis of adult growth hormone deficiency (AGHD) is challenging and often
99 requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is
100 considered the gold standard GHST but is labor-intensive, may cause severe hypoglycemia,
101 and is contraindicated in certain patients. Macimorelin, an orally-active GH secretagogue,
102 could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose.
103 METHODS: This multicenter, open-label, randomized, 2-way crossover trial was designed to
104 validate the efficacy and safety of a single-dose oral macimorelin for AGHD diagnosis
105 compared to the ITT. Subjects with high (n=38), intermediate (n=37), and low (n=39)
106 likelihood for AGHD and healthy, matched controls (n=25) were included in the efficacy
107 analysis of the study.
108 RESULTS: After the first test, 99% of macimorelin and 82% of ITTs were evaluable. Using
109 GH cut-off levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for the ITT, negative
110 agreement was 95.38% (CI 87%-99%), positive agreement was 74.32% (CI 63%-84%),
111 sensitivity was 87%, and specificity was 96%. Upon retesting, reproducibility was 97% for
112 macimorelin (n=33). In post-hoc analyses, a GH cut-off of 5.1 ng/mL for both tests resulted in
113 94% (CI 85-98%) negative agreement, 82% (CI 72-90%) positive agreement, 92% sensitivity
114 and 96% specificity. No serious adverse events were reported for macimorelin.
115 CONCLUSIONS: Oral macimorelin is a simple, well-tolerated, reproducible, and safe
116 diagnostic test for AGHD with comparable accuracy to the ITT. A GH cut-off of 5.1 ng/mL
117 for the macimorelin test provides excellent balance between sensitivity and specificity.
118
119 Clinicaltrials.gov: NCT02558829 5
Macimorelin as a diagnostic test for AGHD 120
121 PRECIS
122 This multicenter, open-label, randomized, 2-way crossover trial of macimorelin vs. the ITT
123 shows that macimorelin is a simple, well-tolerated, reproducible, and safe diagnostic test for
124 AGHD.
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Macimorelin as a diagnostic test for AGHD 144
145 INTRODUCTION
146 Growth hormone (GH) therapy offers clinical benefits in individuals with adult GH deficiency
147 (AGHD) (1-6). However, diagnosing this condition is often challenging and remains a barrier
148 to initiating GH treatment. Random GH levels do not distinguish GH-deficient from GH-
149 sufficient subjects reliably. Accordingly, the diagnosis of AGHD often depends on GH
150 stimulation tests (GHSTs) using agents known to provoke GH release above a certain level in
151 healthy individuals.
152
153 The insulin tolerance test (ITT) is considered the gold standard GHST; however, the test is
154 labor-intensive, may be unpleasant for patients, has potential risks including severe
155 hypoglycemia, and is contraindicated in elderly patients and in those with seizure disorders
156 and heart disease (7,8). Other alternative provocative tests such as the arginine+GH releasing
157 hormone (GHRH), arginine alone and glucagon stimulation tests are either not available in the
158 U.S. or have significant limitations including requiring intramuscular administration, long
159 duration, and/or low accuracy. Thus, there remains an unmet medical need for alternative
160 GHSTs that are safe, reliable, and have received approval by a regulatory authority.
161
162 Ghrelin is known to potently stimulate GH release (9) mediated by specific ghrelin receptors
163 in the pituitary and hypothalamus (10,11). This effect is shared by synthetic agonists of this
164 receptor known as ghrelin mimetics or GH secretagogues. Macimorelin acetate is an oral
165 ghrelin receptor agonist with GH secretagogue (GHS) activity that is readily absorbed and
166 effectively stimulates endogenous GH secretion in healthy volunteers with good tolerability
167 (12). 7
Macimorelin as a diagnostic test for AGHD 168
169 This trial was designed to validate the use of a single-dose oral macimorelin test for diagnosis
170 of AGHD using the ITT as the comparator. The secondary objective was to characterize the
171 safety of macimorelin in this setting.
172
173 MATERIALS AND METHODS
174 This phase III study was an open-label, randomized, multicenter, 2-way crossover study of the
175 macimorelin test versus the ITT (core study). Additionally, a subset of patients (n=33)
176 underwent the macimorelin test twice to evaluate the reproducibility of this test
177 (reproducibility sub-study). The study was conducted in 5 sites in the U.S. and 25 sites across
178 Europe. The protocol was approved by the Institutional Review Boards at each institution and
179 was conducted in compliance with the Declarations of Helsinki and its amendments and the
180 International Conference on Harmonization Guideline for Good Clinical Practices.
181 Recruitment for the study took place between September, 2015 and November, 2016.
182
183 Eligibility criteria
184 Inclusion criteria were age between 18 and 65 years, suspected GH deficiency (GHD) based
185 on one of the following: structural hypothalamic/pituitary disease, surgery or irradiation in
186 these areas, head trauma as an adult, evidence of other pituitary hormone deficiencies, or
187 idiopathic childhood-onset GHD (1). Exclusion criteria were GH therapy within the previous
188 month, having had a GH stimulation test in the previous 7 days, thyroid disorder or
189 hypogonadism that were untreated or not on stable substitution treatment (postmenopausal
190 status was not considered an exclusion criterion), treatment with drugs affecting GH secretion
191 or somatostatin, anti-muscarinic agents, CYP3A4 inducers, ongoing symptomatic severe 8
Macimorelin as a diagnostic test for AGHD 192 psychiatric disorders, Parkinson’s disease, active Cushing’s disease or patients on
193 supraphysiologic glucocorticoid therapy, type 1 diabetes or poorly controlled type 2 diabetes
2 194 mellitus (HbA1c >8%), body mass index (BMI) ≥40 kg/m , participation in a trial with
195 investigational drugs within 30 days, vigorous physical exercise within 24 hours prior to each
196 GHST, clinically significant cardiovascular or cerebrovascular disease, prolonged QT interval
197 (QTc >500 msec), concomitant treatment with drugs that prolong QT/QTc, hepatic or renal
198 dysfunction, history of seizure disorders, immunosuppression, active malignancy other than
199 non-melanoma skin cancer, breastfeeding or positive urine pregnancy test, or women of
200 childbearing age without contraception.
201
202 Subjects with high, intermediate and low likelihood for AGHD were included in the study (at
203 least 25% of AGHD subjects in the high and low likelihood groups). “High likelihood”
204 (Group A) was defined as: a structural hypothalamic or pituitary lesion and low insulin-like
205 growth factor-1 (IGF-1) levels, three or more pituitary hormone deficiencies (PHD) and low
206 IGF-1 levels, or childhood onset GHD with structural lesions and low IGF-1 levels. “Low
207 likelihood” (Group C) was defined as one risk factor for AGHD, such as history of distant
208 traumatic brain injury (TBI), only one pituitary hormone deficiency or childhood-onset
209 isolated GHD. Subjects were included in the “Intermediate likelihood” group (Group B) when
210 not qualifying for the other groups. A group of healthy subjects (Group D) matching Group A
211 subjects by sex, age, BMI, and estrogen status was also included. A subset of subjects from
212 Groups A-C underwent a second macimorelin GHST and were included in the reproducibility
213 sub-study.
214
215 Study procedures 9
Macimorelin as a diagnostic test for AGHD 216 Subjects were randomized to a sequence of both tests (macimorelin GHST then ITT or vice-
217 versa) performed 7-30 days apart and while fasting 8 hours prior to the start and throughout
218 the test. A test was classified as “positive” for GHD when the peak GH value was below the
219 cut-point established a priori, suggesting the patient had the disease. A test was classified as
220 “negative” for GHD when the peak GH value was above that cut-point, suggesting the patient
221 does not have the disease.
222
223 Macimorelin test: Macimorelin oral solution was prepared by trial personnel at a dose of 0.5
224 mg/kg of body weight to be administered within 30 minutes. Blood samples for GH serum
225 levels were collected at pre-dose, then at 30, 45, 60, and 90 minutes (±5-minute window) after
226 administration of macimorelin.
227
228 Insulin Tolerance Test: The ITT was performed with regular human insulin administered
229 intravenously at 0.1 U/kg (0.15 U/kg if BMI >30 kg/m2). Glucose was monitored in capillary
230 or venous blood every 15 minutes until 60 minutes after insulin administration, thereafter
231 every 30 minutes, and when there was evidence of symptomatic hypoglycemia with
232 diaphoresis or cognitive symptoms. As soon as clinical signs of hypoglycemia were achieved,
233 blood for plasma glucose was taken for confirmation, defined as a glucose value below 2.2
234 mmol/L (40 mg/dL). An additional insulin bolus of 0.05 U/kg was administered if a glucose
235 value <2.2 mmol/L (40 mg/dL) and symptomatic hypoglycemia had not been achieved within
236 45 minutes after the initial dose. Blood samples to determine serum GH concentrations were
237 collected at pre-dose, 15, 30, 45, 60, 90 and 120 minutes (±5-minute window) after insulin
238 administration. Intravenous glucose/dextrose was administered if a subject developed severe
239 symptoms of neuroglycopenia, (i.e., seizures). Oral glucose administration was allowed if a 10
Macimorelin as a diagnostic test for AGHD 240 patient had a glucose level below 2.2 mmol/L (40 mg/dL) and moderate symptoms of
241 neuroglycopenia (e.g., confusion).
242
243 Determination of Evaluable Tests: The cut-off values determined a priori for stimulated GH
244 levels measured by the IDS-iSYS hGH assay were 2.8 ng/mL for the macimorelin test and 5.1
245 ng/mL for the ITT based on previously published data (13,14). A Data Review Committee
246 (DRC) that included 4 investigators and representatives from the Sponsor reviewed and
247 qualified each test as “evaluable” or “non-evaluable” prior to the availability of the GH
248 results. Reasons for the DRC to designate a test “non-evaluable” included major deviation in
249 blood sampling, not reaching the target glucose level and symptomatic hypoglycemia (for the
250 ITT), incomplete intake of the dose or vomiting after drinking for macimorelin. Whenever
251 possible, a test declared non-evaluable by the DRC was repeated after at least 7 days. The
252 DRC also reviewed the assignment of study participants to the AGHD likelihood groups A-C.
253
254 GH measurements
255 Serum GH concentrations were measured centrally (Synevo Central Lab, Warsaw, Poland) by
256 a validated immunochemiluminometric assay (IDS-iSYS Human GH, Immunodiagnostic
257 Systems Ltd, UK) (15,16). This assay is standardized to the recombinant GH calibration
258 standard WHO 98/574, and complies with recommendations on assay standardization (17).
259
260 Statistical Analysis
261 Statistical analyses were performed using SAS® (v9.3, SAS Institute, Inc, Cary, NC). All
262 randomized subjects in whom both GHSTs were evaluable were included in the efficacy
263 analyses. Criteria for an evaluable GHST were: a) the DRC adjudicated the GHST as 11
Macimorelin as a diagnostic test for AGHD 264 evaluable, b) a peak GH concentration equal or greater than the cut-off rendered the test
265 evaluable irrespective of the DRC adjudication, and c) for the macimorelin GHST, 45- and 60-
266 minute post-dose GH concentrations were available or imputable categorically. The safety
267 population used for the primary safety analyses included all randomized subjects who took at
268 least one dose of trial medication. It was planned to include at least 110 subjects to achieve 55
269 with GHD as assessed by ITT and 55 passing the ITT for GH test outcomes. The ITT was
270 used as comparator, and the primary measures for diagnostic consistency were ‘percent
271 positive agreement’ and ‘percent negative agreement’. The estimated percent agreements and
272 the two-sided 95% confidence interval (CI) of the percent agreement based on Clopper-
273 Pearson (18) were calculated.
274
275 The accuracy measures were defined as follows:
276
ITT outcome
positive Negative
Macimorelin test positive w U
outcome negative y Z
Total w+y x+z
277
278 Positive percent agreement [%]=100% x w/(w+y)
279 Negative percent agreement [%]=100% x u/(u+z)
280 Overall percent agreement [%]=100% x (w+z)/(w+u+y+z)
281
12
Macimorelin as a diagnostic test for AGHD 282 The primary efficacy measures (negative and positive agreements) based on the following four
283 methods were analyzed by a hierarchical testing procedure with regard to the sampling time
284 for the macimorelin test: 1) Peak GH concentration among all post baseline samples (30, 45,
285 60 and 90 minutes); 2) Highest GH concentration among 45- and 60-minute samples; 3) GH
286 concentration at 60 minutes post-dose; and 4) GH concentration at 45 minutes post-dose.
287 Adverse events (AEs), clinical laboratory results, and ECGs were evaluated by descriptive
288 statistics. QTcF (Fridericia correction) was centrally re-calculated for all ECGs based on the
289 formula QT [msec]/(RR[sec])(1/3) (19).
290
291 For exploratory analyses, sensitivity and specificity for both GHSTs were estimated, assuming
292 all high probability (Group A) AGHD subjects as “true” AGHD subjects and all healthy
293 matching subjects (Group D) as “true” AGHD negative subjects. ROC analysis results are
294 presented based on these assumptions. Reproducibility of the macimorelin test was analyzed
295 by descriptive statistical analyses. Statistical tests were performed two-sided with a type I
296 error (p-value) of α=0.05.
297
298 RESULTS
299 One-hundred-sixty-six screened subjects were eligible and enrolled in the study (137
300 suspected AGHD subjects and 29 healthy subjects). Of these, 157 subjects underwent at least
301 one GHST (safety population), 154 had both GHSTs performed at least once, and in 140
302 subjects both GHSTs were found evaluable by the DRC. Of these, one subject showed no
303 measurable macimorelin plasma levels at the first macimorelin GHST and detectable
304 macimorelin plasma levels and a GH increase during the macimorelin GHST in the
305 reproducibility sub-study. This was attributed to a non-compliance or dosing error and this 13
Macimorelin as a diagnostic test for AGHD 306 patient was removed from the efficacy analysis. The study design and patient disposition is
307 shown in Figure 1.
308
309 Baseline characteristics are shown in Table 1. In 27 of 157 subjects, the ITT provided a peak
310 GH concentration <5.1 ng/mL, without confirmed hypoglycemia. In only 17 of these 27
311 subjects the non-evaluable ITT was repeated, and 4 of the subjects were then classified as ITT-
312 negative; 14 of 27 cases with a non-evaluable ITT could not be included in the efficacy
313 analysis. Only 1 of 154 macimorelin GHSTs was non-evaluable and had to be repeated. In this
314 case, the site had not collected blood samples for GH measurements at the initial macimorelin
315 GHST. Among the 139 subjects of the efficacy population, 74 were classified as GHD and 65
316 as GH sufficient based on the ITT. Thirty-one of the 114 GHD subjects were studied in the
317 US, whereas all subjects in Group D and 83 GHD patients were investigated in Europe.
318
319 Negative and positive agreements between the macimorelin GHST and the ITT
320 Negative agreement was 95.38% (CI 87.10%-99.04%), and positive agreement was 74.32%
321 (CI 62.84%-83.78%) between the macimorelin GHST and the ITT with the pre-specified cut-
322 off points (2.8 ng/mL for the macimorelin GHST and 5.1 ng/mL for the ITT). In a post-hoc
323 analysis using a cut-point of 5.1 ng/mL for both tests, negative agreement was 93.85% (CI
324 84.99%-98.30%), and positive agreement was 82.43% (CI: 71.83%-90.30%). Supplemental
325 Tables 1 and 2 show the performance of the macimorelin GHST using different cut-off points
326 and the hierarchical step-wise approach, respectively.
327
328 Sensitivity and specificity of the macimorelin GHST
14
Macimorelin as a diagnostic test for AGHD 329 Due to the lack of a "standard of truth" to determine the true AGHD status of each participant,
330 sensitivity and specificity for both GHSTs could only be estimated from test outcomes in a
331 subset of the efficacy population: assuming all ‘high likelihood’ AGHD subjects (Group A) as
332 ‘true’ AGHD subjects and all ‘healthy’ matching subjects (Group D) as ‘true’ AGHD negative
333 subjects. When using the pre-defined cut-off points of 2.8 ng/mL for macimorelin, sensitivity
334 was 87%, and specificity was 96%. Figure 2 illustrates the effect of varying GH cut-off points
335 for the macimorelin GHST on the estimated sensitivity and specificity, respectively. The
336 figure shows that increasing the GH cut-off point for the macimorelin GHST between 2.8
337 ng/mL and approximately 8 ng/mL will increase the sensitivity with a minimal effect on the
338 specificity of the test. When using a cut-off point of 5.1 ng/mL, sensitivity and specificity of
339 the macimorelin GHST were 92% and 96%.
340
341 Peak GH response in the macimorelin GHST and ITT by AGHD likelihood Group
342 Higher peak GH was seen in all groups in the macimorelin GHST compared to the ITT
343 (Figure 3A). Moreover, peak GH levels were inversely related to the likelihood of having
344 AGHD. There was a high correlation between peak GH in the ITT and the macimorelin GHST
345 (Figure 3B).
346
347 Reproducibility of the macimorelin GHST
348 The reproducibility of the macimorelin GHST was 94%. No significant differences were
349 found between the peak GH concentrations measured in the core study and in the
350 reproducibility sub-study (n=33). The lack of a difference was shown not only for the entire
351 population of the repeatability study, but also for both subsets of positive and negative GHST
352 outcome in the core study, i.e. stratified for subjects with a peak GH below or above 2.8 15
Macimorelin as a diagnostic test for AGHD 353 ng/mL (Supplemental Table 3), and also for those subjects in groups A, B and C
354 (Supplemental Figure 1). The reproducibility of the macimorelin GHST was also maintained
355 using different cut-off points and the hierarchical step-wise approach (Supplemental Tables 1-
356 2).
357
358 Safety and tolerability
359 No serious adverse events (SAE) were reported following an ITT, one case of a broken arm
360 was reported one day after a macimorelin GHST as unrelated to the test. Other non-SAE were
361 more common and of greater severity during ITT than during the macimorelin GHST (see
362 Supplemental material and Supplemental Table 4).
363
364 DISCUSSION
365 Evaluation of AGHD should be based upon medical history, clinical findings, and using the
366 appropriate GHST for biochemical confirmation, except in patients with panhypopituitarism
367 and low IGF-1 levels (1). The ITT remains the gold standard for evaluation of AGHD but it is
368 only reluctantly performed by some endocrinologists because of the potential risk of
369 hypoglycemia and because it requires resources that may not be available in some settings
370 (20). GHRH+arginine was an alternative to ITT until 2008 when Geref®, the only approved
371 GHRH analog in the U.S., was taken off the market, although it remains available in other
372 countries (14). Recognizing the need for an alternative GHST to the ITT, we sought to
373 validate the use of oral macimorelin as a diagnostic test for AGHD.
374
375 Acylated ghrelin (21) and agonists of its receptor (22,23) have been evaluated as diagnostic
376 tests for AGHD but none of them are commercially available in the U.S. The ghrelin mimetic 16
Macimorelin as a diagnostic test for AGHD 377 macimorelin is a pseudotripeptide with increased oral bioavailability compared to other GH
378 secretagogues (24). Previous studies have shown that a single oral dose induced a strong dose-
379 dependent increase in GH levels lasting 120 minutes, with peak plasma drug concentrations
380 between 50 and 75 min (12,24).
381
382 A previous open-label, crossover, multicenter trial tested the diagnostic accuracy of a single
383 oral dose of macimorelin (0.5 mg/kg) compared to arginine+GHRH in AGHD patients and
384 healthy matched controls (13). Peak GH levels were 2.36±5.69 and 17.71±19.11 ng/mL in
385 AGHD subjects and healthy controls, respectively (p<0.0001), with an optimal GH cut-off
386 ranging between 2.7 ng/mL and 5.2 ng/mL measured by a different
387 immunochemiluminometric assay (Esoterix, LabCorp, Cranford, NJ) than the one used in this
388 study. Unfortunately, after 43 AGHD patients and 10 controls were tested, the GHRH analog
389 Geref Diagnostic® was taken off the market in the U.S. and 10 additional AGHD patients and
390 38 controls were only dosed with macimorelin limiting the validity of the study (13).
391
392 Here, we have validated the use of single-dose oral macimorelin for AGHD diagnosis, using
393 the ITT as the comparator test. Macimorelin induced a robust increase in GH levels in healthy
394 individuals and showed good agreement with the ITT in AGHD patients with a range of pre-
395 test probabilities of having AGHD. The macimorelin test was easy to perform and well-
396 tolerated as it does not depend on the presence of hypoglycemia and only requires collection
397 of four venous blood samples after administration. The high repeatability (94%) and estimated
398 sensitivity (92%) and specificity (96%) when using a GH cut-off of 5.1 ng/mL were
399 remarkable considering that the repeatability of the ITT has been shown to be 90% in one
400 report (25) and to have a coefficient of variation of 58% in another (26). The inverse 17
Macimorelin as a diagnostic test for AGHD 401 relationship between peak GH and the likelihood of having AGHD we found is consistent with
402 published data showing that peak GH levels were inversely related to the number of pituitary
403 deficiencies (27,28).
404
405 In order to minimize the potential for over-diagnosing AGHD, a priori we selected a cut-off
406 point of 2.8 ng/mL, the low end of the range suggested by the previously available data and
407 despite using different GH assays (13). Data from the current study indicate that the optimal
408 cut-off point for macimorelin ranges between 4.6 and 8.1 ng/mL. Using 5.1 ng/mL as the cut-
409 off point resulted in good negative and positive agreement (94% and 82% respectively), with
410 92% sensitivity and 96% specificity. As measured GH concentrations will depend on the GH
411 assay used, it is important to keep in mind that these data are based on a recommended GH
412 cut-off point of 5.1 ng/mL using the IDS-iSYS Human Growth Hormone assay
413 (Immunodiagnostic Systems Ltd., UK). This cut-off point is identical to the cut-off point
414 recommended for the ITT, allowing endocrinologists using a different GH assay to apply a
415 cut-off point relating to the one used for evaluating ITTs in their local laboratory. Applying a
416 higher GH cut-off point than used for the ITT will increase the sensitivity of macimorelin and
417 lead to higher positive agreement with the ITT, based on the higher stimulated GH
418 concentrations in the macimorelin GHST than in the ITT, but this may be associated with a
419 higher risk of over-diagnosing AGHD.
420
421 The macimorelin GHST was safe, not associated with frequent or SAEs that would require
422 specific precautions or close monitoring by medical personnel. The most frequently reported
423 side effect was mild and transient dysgeusia. In a previous study, only one drug-related SAE,
424 an asymptomatic QT interval prolongation on the electrocardiogram resolved spontaneously 18
Macimorelin as a diagnostic test for AGHD 425 within 24 hours in an individual taking citalopram, a drug now known to be associated with
426 QT prolongation (29). In this study, no drug related SAEs were observed and no AE was
427 documented with regards to the QT interval. In general, effects on the QT interval seem to be
428 more pronounced during the ITT as compared to macimorelin. This is in line with a recent
429 report showing QT prolongation in more than 20% of individuals undergoing an ITT (30).
430
431 The safety profile is particularly favorable when compared to the ITT which has potential for
432 inducing severe side effects such as hypoglycemia-related seizure and exacerbation of
433 cardiovascular and cerebrovascular disease. From a clinician’s perspective, this test is also
434 more convenient, less time-consuming and less resource-intensive than the ITT. This may
435 increase the likelihood that at risk patients are offered evaluation for AGHD. Another
436 advantage of the macimorelin GHST is that in some individuals, the ITT had to be repeated
437 for inadequate hypoglycemia, likely due to insulin resistance, whereas 99% of the
438 macimorelin tests were evaluable after the first attempt. The macimorelin GHST is also more
439 convenient than other alternative tests such as the glucagon stimulation test that requires 3-4
440 hours of testing, intramuscular administration, is associated with more side effects (i.e.;
441 nausea, vomiting), and has questionable diagnostic accuracy in overweight/obese patients
442 (31).
443
444 There are limitations to the study. This study is relatively small and it may not yet be an
445 appropriate substitute test for ITT or other provocative tests in all cases until more data is
446 accumulated. For instance, patients with uncontrolled diabetes, elderly and pediatric patients
447 were not evaluated in this trial and further studies are needed in such groups. Hence, the
448 results presented here apply to the specific populations tested here: adults with a history 19
Macimorelin as a diagnostic test for AGHD 449 compatible with AGHD. Also, only a small number of individuals with hypothalamic disease
450 or with a BMI >35 kg/m2 were included in the study, limiting the generalizability of these
451 findings to those groups. Due to the lack of a "standard of truth" to determine the true AGHD
452 status of each participant, it was not possible to measure the true sensitivity and specificity of
453 the test. Strengths of the study include the use of the ITT as a comparator, enrollment of
454 matched healthy controls, evaluating patients with a wide range of likelihood to have AGHD,
455 and a state-of-the-art GH assay measured centrally. Future studies should assess patients
456 suspected to have AGHD and amenable to GH replacement that are over the age of 65 and
457 with a BMI over 40. Also, possible interactions between macimorelin and drugs that prolong
458 QT should be further evaluated.
459
460 In summary, GH stimulation with oral macimorelin is a simple, well-tolerated, reproducible
461 and safe diagnostic test for AGHD, with comparable accuracy to that of the ITT. Evaluating
462 the test at the same GH cut-off of 5.1 ng/mL as used for the ITT limits the risk of a false-
463 positive diagnosis while maintaining a high detection rate of affected patients based on the
464 more potent GH stimulatory effect of macimorelin compared to the ITT.
465
466 Acknowledgments: We thank the patients and healthy volunteers for their participation and
467 the nursing and research staff for their expert professional support in the conduct of this study.
468 We would like to specifically acknowledge the efforts of Anna Olak-Popko, principal
469 investigator at the CRO MTZ Clinical Research in Warsaw, Poland, and her study team,
470 which was fully dedicated to the care for the healthy matched controls in the Phase 3 study.
471 Finally, we also thank Herbert Sindermann and Gilbert Müller, Aeterna Zentaris, for their
472 support and Michael Chen, Tcm Groups Inc, for his statistical advice. 20
Macimorelin as a diagnostic test for AGHD 473
474
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592
593 FIGURE LEGENDS
594 Figure 1. CONSORT diagram of study design and patient disposition.
595
596
597 Insulin tolerance test (ITT), macimorelin stimulation test (MAC).
26
Macimorelin as a diagnostic test for AGHD 598
27
Macimorelin as a diagnostic test for AGHD 599 Figure 2. Specificity and sensitivity of the macimorelin GHST for varying GH cut-off points
600 based on Group A and D subjects
601
602 Error bars represent 95% confidence intervals
603
604
605
606
607
608
609
610
611
612
613 28
Macimorelin as a diagnostic test for AGHD 614 Figure 3A. Peak GH concentrations in MAC and ITT by AGHD likelihood category (n=139))
615
616 The bottom and top of the boxes represent the first and third quartiles. The band inside the box
617 is the median. The cross represents the mean and circles are the individual values. The
618 whiskers are the lowest and the highest data points within 1.5 interquartile range of the lower
619 and upper quartiles.
620
621
622
623
29
Macimorelin as a diagnostic test for AGHD 624 Figure 3B. Scatter plot showing individual subjects peak GH concentrations, both in MAC and
625 ITT (n=139). The majority of the dots above the bisecting line (y=x) demonstrate the higher
626 stimulation potential of MAC as compared to ITT.
627
628
629
630 Insulin tolerance test (ITT), macimorelin stimulation test (MAC), growth hormone (GH). Solid
631 line represents bisecting line. Regression equation y=1.0694x + 2.5216, r2=0.6.
632
30
Macimorelin as a diagnostic test for AGHD 633 TABLES
634 Table 1. Baseline Characteristics
AGHD likelihood Group Parameters Total D: (Safety Population, N = 157) A B C Healthy
N (%) N (%) N (%) N (%) N (%)
Sex Male 25 (59.5) 18 (42.9) 35 (79.6) 15 (51.7) 93 (59.2)
Female 17 (40.5) 24 (57.1) 9 (20.5) 14 (48.3) 64 (40.8)
Total 42 (100) 42 (100) 44(100) 29 (100) 157 (100)
Native Hawaiian or Race 0 (0) 0 (0) 1 (2.3) 0 (0) 1 (0.6) Other Pacific Island
Asian 2 (4.8) 1 (2.4) 2 (4.6) 0 (0) 5 (3.2)
Caucasian 36 (85.7) 36 (85.7) 34 (77.3) 29 (100) 135 (86.0)
Black or African 0 (0) 1 (2.4) 2 (4.6) 0 (0) 3 (1.9) American
Other 4 (9.5) 4 (9.5) 5 (11.4) 0 (0) 13 (8.3)
Total 42 (100) 42 (100) 44 (100) 29 (100) 157 (100)
Ethnicity Hispanic or Latino 4 (9.5) 9 (21.4) 2 (4.6) 0 (0) 15 (9.6)
Not Hispanic or 34 (81) 29 (69.1) 36 (81.8) 29 (100) 128 (81.5) Latino
Not reported 3 (7.1) 4 (9.5) 6 (13.6) 0 (0) 13 (8.3)
31
Macimorelin as a diagnostic test for AGHD Unknown 1 (2.4) 0 (0) 0 (0) 0 (0) 1 (0.6)
Total 42 (100) 42 (100) 44 (100) 29 (100) 157 (100)
Pituitary None 21 (13.4) 12 (7.6) 37 (23.6) -- 70 (44.6) Adenoma
Macroprolactinoma 1 (0.6) 8 (5.1) 1 (0.6) -- 10 (6.4)
Microprolactinoma 1 (0.6) 0 (0) 2 (1.3) -- 3 (1.9)
Non-functioning 15 (9.6) 17 (10.8) 4 (2.6) -- 36 (22.9)
Acromegaly 2 (1.3) 2 (1.3) 0 (0) -- 4 (2.6)
History of 2 (1.3) 3 (1.9) 0 (0) -- 5 (3.2) Cushing’s
CNS tumors None 32 (20.4) 34 (21.7) 39 (22.8) -- 105 (66.7)
Meningioma 0 (0) 5 (3.2) 2 (1.3) -- 7 (4.5)
Craniopharyngioma 9 (5.7) 1 (0.6) 0 (0) -- 10 (6.4)
Medulloblastoma 0 (0) 1 (0.6) 2 (1.3) -- 3 (1.9)
Other 1 (0.6) 1 (0.6) 1 (0.6) -- 3 (1.9)
Other None 26 (16.6) 35 (22.3) 10 (6.4) -- 71 (45.2) abnormalities
Childhood onset 4 (2.6) 2 (1.3) 6 (3.8) -- 12 (7.6) GHD (idiopathic)
Cyst (Rathke’s 4 (2.6) 0 (0) 2 (1.3) -- 6 (3.8) Arachnoid, etc.)
32
Macimorelin as a diagnostic test for AGHD Sheehan’s 1 (0.6) 0 (0) 0 (0) -- 1 (0.6) syndrome
Empty Sella 1 (0.6) 0 (0) 0 (0) -- 1 (0.6)
Head trauma 1 (0.6) 3 (1.9) 21 (13.4) -- 25 (15.9)
Inflammatory 1 (0.6) 0 (0) 0 (0) -- 1 (0.6) disorder
Other 4 (2.6) 4 (2.6) 10 (6.4) -- 18 (11.5)
AGHD likelihood Group
Subgroups D: A B C Total (N = 139) Healthy
N (%) N (%) N (%) N (%) N (%)
BMI class < 30 kg/m² 27 (27.6) 21 (21.4) 27 (27.6) 23 (23.5) 98 (100)
30 - < 35 kg/m² 7 (26.9) 10 (38.5) 7(29.6) 2 (7.7) 26 (100)
35 - < 40 kg/m² 4 (26.7) 6 (40.0) 5 (33.3) 0 (0) 15 (100)
Total 38 (27.3) 37 (26.6) 39 (28.1) 25 (18.0) 139 (100)
Age 18 - ≤ 25 years 7 (29.2) 2 (8.3) 10 (41.7) 5 (20.8) 24 (100)
> 25 years 31 (27.0) 35 (30.4) 29 (25.2) 20 (17.4) 115 (100)
Total 38 (27.3) 37 (26.6) 39 (28.1) 25 (18.0) 139 (100)
635
636
637
33