Advice
Clinical and technical evidence
Clinical and technical evidence
A literature search was carried out for this briefing in accordance with the interim process and methods statement for medtech innovation briefings. This briefing includes the most relevant or best available published evidence relating to the clinical effectiveness of the technology. Further information about how the evidence for this briefing was selected is available on request by contacting mibs@nice.org.uk.
Published evidence
Three studies are summarised in this briefing, including 164 people with confirmed adult growth hormone deficiency (AGHD) or a high, intermediate or low likelihood of AGHD and 73 matched controls. The post-hoc analysis included 41 people with a high likelihood of AGHD and 25 healthy matched controls, both included in the number above.
The studies include 1 randomised crossover trial with a post-hoc analysis of a subgroup from this trial and 1 multicentre open-label study (initially planned as a crossover study). There is a phase 1 randomised controlled trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of macimorelin in healthy adults (Klaus et al. 2020) that is not summarised below.
The clinical evidence and its strengths and limitations are summarised in the overall assessment of the evidence.
Overall assessment of the evidence
The evidence ranges from low to high methodological quality, and most studies had small sample sizes. The phase 3 randomised crossover trial was done in the US and 25 sites across Europe, which included 1 NHS trust. The studies suggest that macimorelin is an effective and safe test for diagnosing AGHD and its accuracy is comparable with alternative tests, including the insulin tolerance test. Further research is needed comparing macimorelin with alternative tests in the UK.
Garcia et al. (2018)
Key outcomes
In total, 139 people were included in the analysis. Of these, 38 were included in the high likelihood group (group A), 37 in the intermediate group (group B) and 39 in the low likelihood group (group C). Group D consisted of 25 healthy matched controls. Using the prespecified growth hormone cut-off levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for the insulin tolerance test, the negative agreement was 95.38% (95% confidence interval [CI] 87.10% to 99.04%) and the positive agreement was 74.32% (95% CI 62.84% to 83.78%) between the 2 groups. Using the 2.8 ng/mL growth hormone cut-off point for macimorelin, sensitivity was 87% and specificity 96%. Increasing the growth hormone cut-off point to 5.1 ng/mL for macimorelin increased the sensitivity to 92% but the specificity remained at 96%. No serious adverse events were reported for macimorelin. Non-serious adverse events were more common and of greater severity for the insulin tolerance test compared with the macimorelin test.
Strengths and limitations
This phase 3 study concluded that macimorelin is a simple, well-tolerated, reproducible and safe test for diagnosing AGHD with accuracy comparable with the insulin tolerance test. The trial has several strengths; it included matched controls and evaluated people with a low, intermediate and high likelihood of having growth hormone deficiency (GHD). A study limitation was that a specific population was evaluated, which may limit the generalisability of the results. The trial was funded by the company and all authors received research support from the company. The authors have also presented the results in the form of a conference abstract (Garcia et al. 2017).
Garcia et al. (2021)
Key outcomes
This was a post-hoc analysis of the Garcia 2018 trial. The performance of the macimorelin test, reported as area under the receiver operating characteristic curve, was not meaningfully affected by age (0.9924), body mass index (BMI; 0.9916) or sex (0.9950) compared with the unadjusted model (0.9924). Using the growth hormone cut-off point of 2.8 ng/mL for macimorelin, estimated sensitivity was 88% and specificity was 97% for the unadjusted model. These values remained the same when adjusting for age and for mean or median BMI. When adjusting for sex, sensitivity was 88% for both males and females, and specificity was 100% for males and 93% for females. Using the growth hormone cut-off point of 5.1 ng/mL for macimorelin, estimated sensitivity was 93% and specificity was 97% for the unadjusted model. These values remained the same when adjusting for age and BMI but changed slightly when adjusting for sex. When evaluating the entire study population, using the same cut-off point of 2.8 ng/mL for both the macimorelin test and the insulin tolerance test resulted in high levels of positive (87.1%), negative (93.6%) and overall (90.7%) agreement between tests. These were higher than agreement levels using a cut-off point of 5.1 ng/mL for both tests. Of the 4 growth hormone cut-off points evaluated, the cut-off point of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the insulin tolerance test at the same cut-off point (87%).
Strengths and limitations
The authors concluded that the macimorelin test performance is robust and not meaningfully affected by age, baseline BMI or sex over a range of growth hormone cut-off points. Limitations include a small sample size and limited generalisability to people aged 65 and over, people with poorly controlled diabetes or people with severe obesity. The study was sponsored by the company.
Garcia et al. (2013)
Study size, design and location
Multicentre open-label study in 50 people with AGHD and 48 healthy matched controls in the US.
Intervention and comparator
Macimorelin compared with arginine plus growth hormone-releasing hormone (GHRH).
Key outcomes
Peak growth hormone levels in the AGHD group were 2.36 ng/mL (standard deviation [SD] 5.69 ng/mL) compared with 17.71 ng/mL (SD 19.11 ng/mL) in the control group (p<0.0001). For macimorelin, the receiver operating characteristic analysis yielded an optimal growth hormone cut-off of 2.7 ng/mL, with 82% sensitivity and 92% specificity. There was a misclassification rate of 13%. In both groups, 58% of people had obesity and peak growth hormone levels were inversely associated with BMI in the control group. Using a separate cut-off point of 6.8 ng/mL for people without obesity and 2.7 ng/mL for people with obesity increased the sensitivity to 86% and reduced the misclassification rate to 11%. In people receiving both tests, macimorelin showed a better discrimination compared with arginine plus GHRH, but this difference was not statistically significant (p=0.29). One serious adverse event, an asymptomatic QT interval prolongation on the electrocardiogram, was reported in a matched control group receiving macimorelin.
Strengths and limitations
The authors concluded that this study showed that macimorelin is safe and effective in diagnosing AGHD, with sensitivity and specificity comparable with other tests. The study was originally designed as a crossover trial of macimorelin compared with arginine plus GHRH. However, after 43 people with AGHD and 10 controls had been tested, the GHRH used in the study became unavailable in the US. The study was completed by testing 10 more people with AGHD and 38 controls with macimorelin alone. People with diabetes, renal or hepatic dysfunction were excluded from the trial, potentially limiting the generalisability of the results. All investigators received research support from Ardana Biosciences, Aeterna Zentaris, or both.
Sustainability
The company did not make any claims around environmental sustainability benefits for macimorelin.
Recent and ongoing studies
The company states that there is an ongoing phase 3 study in paediatrics:
A Research Study of How Well Macimorelin Works to Find Out if Children Have a Lack of Growth Hormone and How Safe it is (DETECT). ClinicalTrials.gov identifier: NCT04786873. Status: recruiting. Indication: growth hormone deficiency. Drug: macimorelin. Estimated completion date: September 2023. Countries: Georgia, Italy, Poland, US.