Macrilen (Page 3 of 4)

14 CLINICAL STUDIES

The diagnostic efficacy of the MACRILEN test was established in a randomized, open-label, single-dose, cross-over study. The objective of the study was to compare the level of agreement between MACRILEN test results and insulin tolerance test (ITT) results in adult patients with different pre-test probability of growth hormone deficiency and healthy control subjects. The four groups of individuals evaluated were:

Group A: Adults with a high likelihood of growth hormone deficiency (GHD)
o
Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or
o
Three or more pituitary hormone deficiencies and low IGF-1, or
o
Childhood onset GHD with structural lesions and low IGF-1.
Group B: Adults with an intermediate likelihood of GHD
o
Eligible subjects not qualifying for either high or low likelihood.
Group C: Adults with a low likelihood of GHD
o
One risk factor for GHD only, such as history of distant traumatic brain injury or one pituitary hormone deficiency only with otherwise normal pituitary function, or
o
Isolated idiopathic childhood onset GHD without additional pituitary deficits.
Group D: Healthy adult controls
o
Healthy subjects matching Group A subjects by sex, age ± 5 years, body mass index (BMI ± 2 kg/m2), and estrogen status (females only).

For both the ITT and the MACRILEN test, serum concentrations of growth hormone were measured at 30, 45, 60, and 90 minutes after drug administration. The test was considered positive (i.e., growth hormone deficiency diagnosed) if the maximum serum GH level observed after stimulation was less than the pre-specified cut point value of 2.8 ng/mL for the MACRILEN test or 5.1 ng/mL for the ITT.

The level of negative and positive agreement between the results of the ITT and the MACRILEN test was used to evaluate the performance of the MACRILEN test. In the study, the ITT is used as the benchmark (i.e., a negative ITT indicates absence of disease and a positive ITT indicates presence of disease). Negative agreement is the proportion of subjects with a negative ITT (i.e., those who do not have GHD per the ITT) who also have a negative MACRILEN test. With a high level of negative agreement, the MACRILEN test will not wrongly diagnose an individual without GHD per the ITT as having GHD. Positive agreement is the proportion of subjects with a positive ITT (i.e., those who have GHD per the ITT) who also have a positive MACRILEN test. With a high level of positive agreement, the MACRILEN test will not wrongly diagnose an individual with GHD per the ITT as not having GHD. The agreement measures are defined mathematically below (see Table 2).

Table 2: Definition of Agreement between ITT and MACRILEN

Insulin Tolerance Test

Total

+

MACRILEN

+

a

b

a+b

Positive Agreement (%)=100% x a/(a+c)

c

d

c+d

Negative Agreement (%)=100% x d/(b+d)

Total

a+c

b+d

a+b+c+d

Overall Agreement (%)=100% x (a+d)/(a+b+c+d)

Results

One hundred and fifty-seven subjects underwent at least one of the two tests in this study, 59% were male, 41% female, and 86% of white origin. The median age was 41 years (range: 18 – 66 years) and body mass index 27.5 kg/m2 (range: 16 – 40 kg/m2). The study relied on a cross-over design and each participant was to undergo the two diagnostic tests and serve as his or her own control. Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C, and 25 (18%) in Group D. One out of 154 MACRILEN tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved.

Two-by-two tables presenting the pre-specified primary analysis results for the ITT and MACRILEN test are shown below for all subjects (Groups A, B, C, and D combined) and for each group separately (see Table 3). The estimates for negative and positive agreement between MACRILEN and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between MACRILEN and the ITT in subjects with intermediate or low risk (Groups B and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints).

Table 3: Diagnostic Outcomes for MACRILEN and the ITT in all Subjects (Groups A, B, C, and D) and in Each Group Separately

All Subjects

Insulin Tolerance Test

Total

Agreement Between

+

ITT and MACRILEN

MACRILEN

+

55

4

59

Positive

74%

19

62

81

Negative

94%

Total

74

66

140

Overall

84%

Group A
High likelihood of AGHD

Insulin Tolerance Test

Total

+

MACRILEN

+

33

0

33

Positive

89%

4

1

5

Negative

100%

Total

37

1

38

Overall

89%

Group B
Intermediate likelihood of AGHD

Insulin Tolerance Test

Total

+

MACRILEN

+

20

1

21

Positive

67%

10

6

16

Negative

86%

Total

30

7

37

Overall

70%

Group C
Low likelihood of AGHD

Insulin Tolerance Test

Total

+

MACRILEN

+

2

2

4

Positive

33%

4

32

36

Negative

94%

Total

6

34

40

Overall

85%

Group D
Healthy control

Insulin Tolerance Test

Total

+

MACRILEN

+

0

1

1

Positive

0%

1

23

24

Negative

96%

Total

1

24

25

Overall

92%

Repeatability was tested in a subset of 34 subjects who underwent two MACRILEN tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%).

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