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

Growth Hormone Deficiency Clinical Trial

— foresiGHt  

Official title:

foresiGHt: A Multicenter, Randomized, Parallel-arm, Placebo-controlled (Double- Blind) and Active-controlled (Open-label) Trial to Compare the Efficacy and Safety of Once-weekly Lonapegsomatropin With Placebo and a Daily Somatropin Product in Adults With Growth Hormone Deficiency

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04615273
• Other study ID #: TCH-306
• Secondary ID: 2020-000929-42
• Status: Completed
• Phase: Phase 3
• Start date: December 3, 2020
• Est. completion date: December 1, 2023

Study information

• Verified date: December 2023
• Source: Ascendis Pharma A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A 38 week dosing trial of lonapegsomatropin, a long-acting growth hormone product, administered once-a-week versus placebo-control. A daily somatropin product arm is also included to assist clinical judgement on the trial results. Approximately 240 adults (males and females) with growth hormone deficiency will be included. Randomization will occur in a 1:1:1 ratio (lonapegsomatropin : placebo : daily somatropin product). This is a global trial that will be conducted in, but not limited to, the United States, Europe, and Asia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 264
• Est. completion date: December 1, 2023
• Est. primary completion date: November 2, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Years to 80 Years

Eligibility

Inclusion Criteria

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

2. 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).

A. For all countries except Japan: Subjects must satisfy at least one of the following criteria:

1. Insulin tolerance test: peak GH =5 ng/mL

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

• i. BMI =30 kg/m2: peak GH =3 ng/mL

• ii. BMI >30 kg/m2: peak GH =1 ng/mL

3. Three or four pituitary axis deficiencies (i.e., adrenal, thyroid, gonadal, and/or vasopressin; not including GH) with 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/m2, peak GH <11 ng/mL

• ii. BMI =25-=30 kg/m2, peak GH <8 ng/mL

• iii. BMI >30 kg/m2, peak GH <4 ng/mL

B. For Japan only: Subjects with AGHD and deficiency of at least one non-GH pituitary hormones need to satisfy one of the following GH stimulation tests. Subjects with GHD 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 subjects 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 subjects not on glucocorticoid replacement therapy, documentation of adequate adrenal function at screening defined.

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 subjects 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 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 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. Subjects 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 subject'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. Subjects with acromegaly without remission / with documented remission less than 24 months prior to screening.

6. Subjects with Cushing's disease without remission / with documented remission less than 24 months prior to screening.

7. Subjects with prior cranial irradiation or hypothalamic-pituitary surgery: the procedure took place less than 12 months prior to screening.

8. eGFR <60 mL/min/1.73m2 determined based on Modification of Diet in Renal Disease (MDRD) equation.

9. Hepatic transaminases (i.e., AST or ALT) >3 times the upper limit of normal.

10. Heart failure NYHA class 3 or greater (NYHA 1994).

11. QTcF = 451 milliseconds on 12-lead 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, GLP-1 receptor agonists, 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 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 subjects 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.

Related Conditions & MeSH terms

• Dwarfism, Pituitary
• Endocrine System Diseases
• Growth Hormone Deficiency
• Hormone Deficiency

Intervention

Drug:
• Lonapegsomatropin
Due to the different hGH dose requirements, depending on subject's age and concomitant use of oral estrogen, this trial has 3 dosing groups per arm, followed by gradual increasing dose titration to a target maintenance dose.

Other:
• Placebo
The placebo for lonapegsomatropin drug product will contain the same excipients as lonapegsomatropin drug product but does not contain lonapegsomatropin itself. The placebo solution will be administered by SC injection via syringe and needle. Due to the different hGH dose requirements, depending on subject's age and concomitant use of oral estrogen, this trial has 3 dosing groups and the placebo will receive the same dose volume as if they would have been randomized to once-weekly lonapegsomatropin.

Drug:
• Somatropin
Somatropin solution is provided in a pre-filled pen intended for daily subcutaneous injection. Due to the different hGH dose requirements, depending on subject's age and concomitant use of oral estrogen, this trial has 3 dosing groups per arm, followed by gradual increasing dose titration to a target maintenance dose.

Locations

Country	Name	City	State
Armenia	Ascendis Pharma Investigational Site	Yerevan
Australia	Ascendis Pharma Investigational Site	Box Hill	Victoria
Australia	Ascendis Pharma Investigational Site	Fitzroy	Victoria
Australia	Ascendis Pharma Investigational Site	Parkville	Victoria
Australia	Ascendis Pharma Investigational Site	Perth	Western Australia
Australia	Ascendis Pharma Investigational Site	Saint Leonards	New South Wales
Australia	Ascendis Pharma Investigational Site	Sydney	New South Wales
Canada	Ascendis Pharma Investigational Site	Halifax	Nova Scotia
Canada	Ascendis Pharma Investigational Site	Vancouver	British Columbia
Denmark	Ascendis Pharma Investigational Site	København
France	Ascendis Pharma Investigational Site	Lyon
France	Ascendis Pharma Investigational Site	Marseille
France	Ascendis Pharma Investigational Site	Nantes
France	Ascendis Pharma Investigational Site	Paris
Georgia	Ascendis Pharma Investigational Site	Tbilisi
Georgia	Ascendis Pharma Investigational Site	Tbilisi
Germany	Ascendis Pharma Investigational Site	München	Bayern
Greece	Ascendis Pharma Investigational Site	Athens	Attica
Greece	Ascendis Pharma Investigational Site	Athens	Attica
Greece	Ascendis Pharma Investigational Site	Thessaloníki	Central Macedonia
Greece	Ascendis Pharma Investigational Site	Thessaloníki
Israel	Ascendis Pharma Investigational Site	Beer Sheva
Israel	Ascendis Pharma Investigational Site	Haifa
Israel	Ascendis Pharma Investigational Site	Petah Tikva
Israel	Ascendis Pharma Investigational Site	Tel Aviv
Italy	Ascendis Pharma Investigational Site	Genova
Italy	Ascendis Pharma Investigational Site	Rome
Italy	Ascendis Pharma Investigational Site	Rome
Italy	Ascendis Pharma Investigational Site	Rozzano
Japan	Ascendis Pharma Investigational Site	Chiba
Japan	Ascendis Pharma Investigational Site	Fukuoka
Japan	Ascendis Pharma Investigational Site	Ishikawa	Okinawa
Japan	Ascendis Pharma Investigational Site	Kagoshima
Japan	Ascendis Pharma Investigational Site	Kashihara	Nara
Japan	Ascendis Pharma Investigational Site	Kawasaki
Japan	Ascendis Pharma Investigational Site	Kawasaki	Kanagawa
Japan	Ascendis Pharma Investigational Site	Kobe	Hyogo
Japan	Ascendis Pharma Investigational Site	Matsumoto	Nagano
Japan	Ascendis Pharma Investigational Site	Nagakute
Japan	Ascendis Pharma Investigational Site	Okayama
Japan	Ascendis Pharma Investigational Site	Osaka
Japan	Ascendis Pharma Investigational Site	Suita	Osaka
Japan	Ascendis Pharma Investigational Site	Tokyo
Japan	Ascendis Pharma Investigational Site	Yamagata
Japan	Ascendis Pharma Investigational Site	Yokohama	Kanagawa
Japan	Ascendis Pharma Investigational Site	Yokohama	Kanagawa
Korea, Republic of	Ascendis Pharma Investigational Site	Seoul
Korea, Republic of	Ascendis Pharma Investigational Site	Seoul
Korea, Republic of	Ascendis Pharma Investigational Site	Seoul
Korea, Republic of	Ascendis Pharma Investigational Site	Suwon
Malaysia	Ascendis Pharma Investigational Site	George Town
Malaysia	Ascendis Pharma Investigational Site	Kota Bharu
Malaysia	Ascendis Pharma Investigational Site	Melaka
Malaysia	Ascendis Pharma Investigational Site	Putrajaya
Netherlands	Ascendis Pharma Investigational Site	Leiden
New Zealand	Ascendis Pharma Investigational Site	Palmerston North	Manawatu-Wanganui
New Zealand	Ascendis Pharma Investigational Site	Wellington
Poland	Ascendis Pharma Investigational Site	Kraków
Poland	Ascendis Pharma Investigational Site	Lódz
Poland	Ascendis Pharma Investigational Site	Poznan
Poland	Ascendis Pharma Investigational Site	Warsaw
Poland	Ascendis Pharma Investigational Site	Wroclaw
Romania	Ascendis Pharma Investigational Site	Bucharest
Romania	Ascendis Pharma Investigational Site	Iasi
Romania	Ascendis Pharma Investigational Site	Timisoara
Serbia	Ascendis Pharma Investigational Site	Belgrade
Serbia	Ascendis Pharma Investigational Site	Kragujevac
Slovakia	Ascendis Pharma Investigational Site	Bratislava
Slovakia	Ascendis Pharma Investigational Site	Lubochna
Spain	Ascendis Pharma Investigational Site	Alicante
Spain	Ascendis Pharma Investigational Site	Barcelona
Spain	Ascendis Pharma Investigational Site	Barcelona
Spain	Ascendis Pharma Investigational Site	Madrid
Spain	Ascendis Pharma Investigational Site	Santiago De Compostela
Spain	Ascendis Pharma Investigational Site	Sevilla
Turkey	Ascendis Pharma Investigational Site	Ankara
Turkey	Ascendis Pharma Investigational Site	Antalya
Turkey	Ascendis Pharma Investigational Site	Aydin
Turkey	Ascendis Pharma Investigational Site	Izmir
Turkey	Ascendis Pharma Investigational Site	Izmit
Turkey	Ascendis Pharma Investigational Site	Kayseri
Ukraine	Ascendis Pharma Investigational Site	Ivano-Frankivs'k
Ukraine	Ascendis Pharma Investigational Site	Kharkiv
Ukraine	Ascendis Pharma Investigational Site	Kyiv
Ukraine	Ascendis Pharma Investigational Site	Kyiv
Ukraine	Ascendis Pharma Investigational Site	Kyiv
Ukraine	Ascendis Pharma Investigational Site	Vinnytsya
United Kingdom	Ascendis Pharma Investigational Site	Cardiff
United Kingdom	Ascendis Pharma Investigational Site	Coventry
United Kingdom	Ascendis Pharma Investigational Site	Leeds
United States	Ascendis Pharma Investigational Site	Birmingham	Alabama
United States	Ascendis Pharma Investigational Site	Boston	Massachusetts
United States	Ascendis Pharma Investigational Site	Chicago	Illinois
United States	Ascendis Pharma Investigational Site	Dallas	Texas
United States	Ascendis Pharma Investigational Site	Dearborn	Michigan
United States	Ascendis Pharma Investigational Site	Fresno	California
United States	Ascendis Pharma Investigational Site	Indianapolis	Indiana
United States	Ascendis Pharma Investigational Site	Las Vegas	Nevada
United States	Ascendis Pharma Investigational Site	Los Angeles	California
United States	Ascendis Pharma Investigational Site	Los Angeles	California
United States	Ascendis Pharma Investigational Site	Morehead City	North Carolina
United States	Ascendis Pharma Investigational Site	New York	New York
United States	Ascendis Pharma Investigational Site	New York	New York
United States	Ascendis Pharma Investigational Site	Palo Alto	California
United States	Ascendis Pharma Investigational Site	Phoenix	Arizona
United States	Ascendis Pharma Investigational Site	Pittsburgh	Pennsylvania
United States	Ascendis Pharma Investigational Site	Portland	Oregon
United States	Ascendis Pharma Investigational Site	Reno	Nevada
United States	Ascendis Pharma Investigational Site	Rochester	Minnesota
United States	Ascendis Pharma Investigational Site	Saint Louis	Missouri
United States	Ascendis Pharma Investigational Site	San Antonio	Texas
United States	Ascendis Pharma Investigational Site	Seattle	Washington
United States	Ascendis Pharma Investigational Site	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Ascendis Pharma Endocrinology Division A/S

Countries where clinical trial is conducted

United States,  Armenia,  Australia,  Canada,  Denmark,  France,  Georgia,  Germany,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Netherlands,  New Zealand,  Poland,  Romania,  Serbia,  Slovakia,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline in Trunk Percent Fat	Change from baseline in trunk percent fat (as assessed by dual-energy x ray absorptiometry [DXA]) at Week 38	38 weeks
Secondary	Incidence of Treatment-Emergent Adverse Events	To evaluate the safety and tolerability of once-weekly lonapegsomatropin in adults with GHD	38 weeks
Secondary	Evaluate serum hGH, lonapegsomatropin, and mPEG levels	To evaluate the pharmacokinetics (PK) of once-weekly lonapegsomatropin in adults with GHD	38 weeks
Secondary	Evaluate serum IGF-1 and IGFBP-3 and IGF-1 SDS and IGFBP-3 SDS	To evaluate the pharmacodynamics (PD) of once-weekly lonapegsomatropin in adults with GHD	38 weeks
Secondary	Change from Baseline in Trunk Fat Mass	Change from baseline in trunk percent fat (as assessed by dual-energy x ray absorptiometry [DXA]) compared to daily Somatropin at Week 38	38 weeks
Secondary	Change from Baseline in Total Body Lean Mass	Change from baseline in total body lean mass (as assessed by dual-energy x ray absorptiometry [DXA]) compared to daily Somatropin at Week 38	38 weeks