A Trial to Compare the Efficacy and Safety of Once-weekly Lonapegsomatropin With Placebo and a Daily Somatropin Product in Adults With Growth Hormone Deficiency

1. Age between 23 and 80 years, inclusive, at screening.

2. Adult Growth Hormone Deficiency (AGHD) Diagnosis Criteria

   • For adult-onset AGHD: documented history of structural hypothalamic-pituitary disease, hypothalamic-pituitary surgery, cranial irradiation, 1-4 non-GH pituitary hormone deficiencies, a proven genetic cause of GHD, or traumatic brain injury (TBI).
   • Participants with childhood-onset GHD must have had GH axis re-assessed at final height.
   • In participants with TBI as a cause of GHD, GHD must be confirmed by GH -stimulation testing performed at least 12 months after the injury.

   A. For all countries except Japan: participants must have satisfied at least one of the following criteria:

   1. Insulin tolerance test: peak growth hormone (GH) \<=5 ng/mL

   2. Glucagon stimulation test according to body mass index (BMI)

      • i. BMI \<=30 kg/m\^2: peak GH \<=3 ng/mL
      • ii. BMI >30 kg/m\^2: peak GH \<=1 ng/mL
   3. Three or four pituitary axis deficiencies (i.e., adrenal, thyroid, gonadal, and/or vasopressin; not including GH) with insulin-like growth factor-1 standard deviation score (IGF-1 SDS) \<= -2.0 at screening
   4. Macimorelin test: peak GH \<=2.8 ng/mL

   5. Growth hormone releasing hormone (GHRH) + arginine test according to BMI:

      • i. BMI \<25 kg/m\^2, peak GH \<11 ng/mL
      • ii. BMI >=25-\<=30 kg/m\^2, peak GH \<8 ng/mL
      • iii. BMI >30 kg/m\^2, peak GH \<4 ng/mL

   B. For Japan only: Participants with AGHD and deficiency of at least one non-GH pituitary hormones need to satisfy one of the following GH stimulation tests. Participants with GHD without additional non-GH pituitary hormone deficiencies with or without and evidence of intracranial structure disorder need to satisfy at least 2 of the following stimulation tests:

   1. Insulin tolerance test: peak GH \<=1.8 ng/mL
   2. Glucagon test: peak GH \<=1.8 ng/mL
   3. Growth Hormone Releasing Peptide-2 (GHRP-2) tolerance test: peak GH \<=9 ng/mL
3. IGF-1 SDS \<= -1.0 at screening as measured by central laboratory.
4. hGH treatment naïve or no exposure to hGH therapy or GH secretagogue for at least 12 months prior to screening.
5. For participants on hormone replacement therapies for any hormone deficiencies other than GH (e.g., adrenal, thyroid, estrogen, testosterone) must be on adequate and stable doses for >=6 weeks prior to and throughout screening.
6. For participants not on glucocorticoid replacement therapy, documentation of adequate adrenal function at screening defined as: morning (6:00-10:00 AM) serum cortisol >15.0 mcg/dL (measured at central laboratory) and/or adrenocorticotropic hormone (ACTH) stimulation test or insulin tolerance test with serum cortisol >18.0 mcg/dL at or within 90 days prior to screening.
7. For males not on testosterone replacement therapy: morning (6:00 - 10:00AM) total testosterone within normal limits for age.
8. On a stable diet and exercise regime at screening with no intention to modify diet or exercise pattern during the trial, i.e., no weight reduction program intended during the trial or within the last 90 days prior to or through screening.
9. No plans to undergo bariatric surgery during the trial.
10. Fundoscopy at screening without signs/symptoms of intracranial hypertension or diabetic retinopathy above stage 2 / moderate or above or any other retinal disease contraindicated to growth hormone therapy. For participants with a diagnosis of diabetes mellitus at screening, this must be documented with a fundus photograph.
11. Able and willing to provide a written informed consent and authorization for protected health information (PHI) disclosure in accordance with Good Clinical Practice (GCP).
12. Serum free thyroxine (fT4) in the normal range at screening as measured by central laboratory.

Exclusion Criteria

1. Known Prader-Willi Syndrome and/or other genetic diseases that may have an impact on an endpoint.

2. Diabetes mellitus at screening if any of the following criteria are met:

   1. Poorly controlled diabetes, defined as HbA1c >7.5% at screening.
   2. Diabetes mellitus (defined as HbA1c >=6.5% and/or fasting plasma glucose >=126 mg/dL and/or plasma glucose >=200 mg/dL two hours after oral glucose tolerance test) diagnosed \<26 weeks prior to screening
   3. Change in diabetes regimen (includes dose adjustment) within \<90 days prior and throughout screening
   4. Use of any diabetes drugs other than metformin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors for a cumulative duration of greater than 4 weeks within 12 months prior to screening
   5. Diabetes-related complications at screening (i.e., nephropathy as judged by the investigator, neuropathy requiring pharmacological treatment, retinopathy stage 2/moderate and above within 90 days prior to screening or during screening)

3. Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:

   1. Resection of in situ carcinoma of the cervix uteri
   2. Complete eradication of squamous cell or basal cell carcinoma of the skin
   3. Participants with GHD attributed to treatment of intracranial malignant tumors or leukemia, provided that a recurrence-free survival period of at least 5 years prior to screening is documented in the participant's file (based on a Magnetic Resonance Imaging (MRI) result for intracranial malignant tumors)
4. Evidence of growth of pituitary adenoma or other benign intracranial tumor within the last 12 months before screening.
5. Participants with acromegaly without remission / with documented remission less than 24 months prior to screening.
6. Participants with Cushing's disease without remission / with documented remission less than 24 months prior to screening.
7. Participants with prior cranial irradiation or hypothalamic-pituitary surgery: the procedure was to take place less than 12 months prior to screening.
8. Estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73m\^2 determined based on Modification of Diet in Renal Disease (MDRD) equation.
9. Hepatic transaminases (i.e., aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) >3 times the upper limit of normal.
10. Heart failure New York Heart Association (NYHA) class 3 or greater (NYHA 1994).
11. Q-T interval, corrected by Fridericia's method (QTcF) >= 451 milliseconds on 12-lead electrocardiogram (ECG) at screening.
12. Poorly controlled hypertension, defined as supine systolic blood pressure >159 mmHg and/or supine diastolic blood pressure >95 mmHg at screening.
13. Cerebrovascular accident within 5 years prior to screening.
14. Anabolic steroids (other than gonadal steroid replacement therapy) or oral/intravenous/intramuscular corticosteroids within 90 days prior to or throughout screening.
15. Currently using or have used within 26 weeks prior to screening any weight-loss or appetite-suppressive medications including orlistat, zonisamide, lorcaserin, bupropion, topiramate, sibutramine, stimulants, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-dependent glucose cotransporters (SGLT-2) inhibitors or medications that affects IGF-1 or GH measurements including cabergoline at doses above 0.5 mg weekly or bromocriptine at doses above 20 mg weekly.
16. Known history of hypersensitivity and/or idiosyncrasy to any of the test compounds (somatropin) or excipients employed in this trial.
17. Known history of neutralizing anti-hGH antibodies.
18. Inability to undergo scanning by dual-energy x-ray absorptiometry (DXA) or a non-interpretable DXA scan at screening.
19. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile) and not using adequate contraceptive methods.
20. Male participants must use a condom, or his female partner of childbearing potential must use an effective form of contraception as described above, from the beginning of screening to the last trial visit.
21. Known substance abuse or known (or previous) eating disorders, including anorexia nervosa, bulimia and severe gastrointestinal disease affecting normal eating (as judged by the investigator).
22. Any disease or condition that, in the judgement of the investigator, may make the subject unlikely to comply with the requirements of the trial or any condition that presents undue risk from the investigational product or procedures.
23. Participation in another interventional clinical trial involving an investigational compound within 26 weeks prior to screening or in parallel to this trial.
24. Currently using or have used within the last 3 days prior to screening: biotin >0.03 mg/day from supplements
25. Known history of positive results of tests for human immunodeficiency virus (HIV) antibodies or hepatitis B and/or C (exceptions if vaccinated towards Hepatitis B virus and Hepatitis C virus).
26. Any of the following: acute critical illness, and complications following open heart surgery, abdominal surgery, multiple accidental traumas, acute respiratory failure, or similar conditions within 180 days prior to screening.