A trial to compare lonapegsomatropin (TransCon hGH) administered once a week and standard daily hGH replacement therapy over 52 weeks in Japanese prepubertal hGH-treatment naive children with growth hormone deficiency (GHD)

JRCT ID: jRCT2031200340

Registered date:02/02/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Pediatric growth hormon deficiency
• Date of first enrollment: 14/06/2021
• Target sample size: 50
• Study type: Interventional

Intervention(s)

<Main period>
Lonapegsomatropin will be administered as once weekly subcutaneous (SC) injections of 0.24 mg hGH/kg/week using GH Auto-Injector.
Genotropin will be administered as daily SC injections in a standard dose of 0.24 mg hGH/kg/week.
The total weekly dose will be equally split into 7 daily doses of 0.034 mg hGH/kg/day. A commercially approved injection device will be used for administration of the drug.
<Extension period>
Lonapegsomatropin will be administered as once weekly subcutaneous (SC) injections of 0.24 mg hGH/kg/week using GH Auto-Injector.
<Treatment experienced subjects>
Lonapegsomatropin will be administered as once weekly subcutaneous (SC) injections of 0.24 mg hGH/kg/week using GH Auto-Injector.

Outcome(s)

• Primary Outcome: Annualized Height Velocity at 52 weeks

Secondary Outcome

<Main period>
- Annualized HV for the lonapegsomatropin and the daily Genotropin over 52 weeks
- Change in HT SDS from baseline over 52 weeks for the lonapegsomatropin and the daily Genotropin
- Incidence of AEs
- Local tolerability (assessed by the subjects, the parents/legally acceptable representatives and the investigator)
- Incidence of anti-hGH antibodies including neutralizing antibodies as needed (both cohorts) and incidence of anti-PEG and anti lonapegsomatropin antibody formation (in lonapegsomatropin subjects)
- Parameters of glucose metabolism [fasting glucose and hemoglobin A1c (HbA1c)] and lipid parameters
- Hormone levels: thyroid status and morning cortisol
- All other hematology and biochemistry blood parameters
- Electrocardiogram (ECG) at Visit 5 (main period) near time to maximum concentration (Tmax) of hGH
- Results of the physical examinations, vital sign measurements
- Bone age at 52 weeks
- Serum hGH levels
- Serum lonapegsomatropin, mPEG levels (in lonapegsomatropin subjects)
- Serum IGF-1, IGFBP-3 levels, IGF-1 SDS and IGFBP-3 SDS
- Proportion of subjects with IGF-1 SDS level 0-2

<Extension period>
Data collected in the extension period will support the following secondary efficacy, safety, and PK/PD endpoints.
- Annualized HV over 156 weeks
- Change in HT SDS from baseline over 156 weeks
- Incidence of AEs
- Local tolerability (assessed by the subjects, the parents/legally acceptable representatives and the investigator)
- Incidence of anti-hGH antibodies including neutralizing antibodies as needed and incidence of anti-PEG and anti-lonapegsomatropin antibody formation
- Parameters of glucose metabolism (HbA1c) and lipid parameters
- Hormone levels: thyroid status and morning cortisol
- All other hematology and biochemistry blood parameters
- Electrocardiogram (ECG)
- Results of the physical examinations, vital sign measurements
- Bone age at 156 weeks
- Serum IGF-1, IGFBP-3 levels, IGF-1 SDS and IGFBP-3 SDS
- Proportion of subjects with IGF-1 SDS level 0-2
- Serum mPEG level

<Treatment experienced subjects>
- Annualized HV over 104 weeks
- Change in HT SDS from baseline over 104 weeks
- Incidence of AEs
- Local tolerability (assessed by the subjects, the parents/legally acceptable representatives and the investigator)
- Incidence of anti-hGH antibodies including neutralizing antibodies as needed and incidence of anti-PEG and anti-lonapegsomatropin antibody formation
- Parameters of glucose metabolism (fasting glucose and HbA1c) and lipid parameters
- Hormone levels: thyroid status and morning cortisol
- All other hematology and biochemistry blood parameters
- Electrocardiogram (ECG)
- Results of the physical examinations, vital sign measurements
- Bone age at 104 weeks
- Serum hGH, lonapegsomatropin, and mPEG levels
- Serum IGF-1, IGFBP-3 levels, IGF-1 SDS and IGFBP-3 SDS
- Proportion of subjects with IGF-1 SDS level 0-2

Key inclusion & exclusion criteria

• Age minimum: >= 3age old
• Age maximum: <= 16age old
• Gender: Both

Include criteria

Main period
<Treatment naive subjects>
1) Prepubertal Japanese children with GHD (either isolated or as part of a multiple pituitary hormone deficiency) in Tanner stage 1 aged (at randomization):
Boys: 3 - 12 years, inclusive
Girls: 3 - 11 years, inclusive
2) Impaired HT:
A. Defined as at least 2.0 standard deviation score (SDS) below the mean HT for chronological age and sex (HT SDS <= -2.0) according to the Japanese year 2000 national growth survey reference data
B. For subjects with HT SDS > -2.0, who have benign, organic, intracranial lesions (such as Rathke's cleft cyst) causing deficiency of at least one pituitary hormone in addition to GH, if
a. the growth velocity is <= 1.5 SD below the age-appropriate mean in the normal population over at least 1 year (or 6 months with medical monitor confirmation) prior to screening
b. and with appropriate documentation of growth velocity as confirmed by the medical monitor
3) Body mass index (BMI) within +/- 2.0 SD of the mean BMI for chronological age and sex according to the Japanese year 2000 national growth survey, or BMI within +/- 2.0 SD of the mean BMI for bone age and sex
4) Diagnosis of GHD confirmed by GH stimulation tests:
A. For all subjects except those listed in section B below:
Confirmed by at least two different GH stimulation tests with a peak GH level of <= 6.0 ng/mL (for tests using insulin, arginine, clonidine, glucagon, or L-Dopa as the stimuli), or <= 16 ng/mL [when growth hormone-releasing peptide 2 (GHRP-2) is the stimulus], determined with a validated assay.
Well-documented historical tests (with properly recorded sampling times and results as well as documented euthyroid status of the subject) performed within approximately 6 months prior to Screening can be accepted to replace any or all of the GH stimulation tests.
B. For subjects with organic brain disease, deficiency of a pituitary hormone other than GH or a documented history of symptomatic hypoglycemia:
Confirmation as in A above however, if deemed appropriate by the Medical Monitor, with one GH stimulation test rather than two
5) Bone age at least 6 months less than chronological age (X ray may have been taken within approximately 6 months prior to Screening may be accepted, the X-ray or digital image should be sent to the central reader)
6) Baseline IGF-1 level of at least 1.0 SD below the mean IGF-1 level standardized for age and sex (IGF-1 SDS <= -1.0) according to the central laboratory reference values
7) Normal fundoscopy at Screening (without signs/symptoms of intracranial hypertension)
8) Children with multiple hormonal deficiencies must be on stable replacement therapy (stable dose and normal blood hormone levels) for other hypothalamo-pituitary axes for at least approximately 3 months. Thyroid replacement therapy for thyroid hormone deficiency must be instituted approximately 6 months (and be stable for approximately 3 months) prior to Screening. Temporary adjustment of glucocorticoid replacement therapy, as appropriate, is acceptable
9) Normal 46 XX karyotype for girls (results prior to Screening may be accepted)
10) Written, signed informed consent of the parents or legally acceptable representatives of the subject and written assent of the subject (if the subject is able to read, understand, and sign)

<Extension period>
1) Children who have completed main period
2) Children who have not permanently discontinued investigational product in the main period
3) Written, signed informed consent of the parents or legally acceptable representatives of the subject and written assent of the subject (if the subject is able to read, understand, and sign)

<Treatment experienced subjects>
1) Investigator-determined GHD diagnosis together with at least two of the following prior to the historical initiation of daily hGH therapy:
a. Two GH stimulation tests with a peak GH level of <= 6.0 ng/mL (for tests using insulin, arginine, clonidine, glucagon, or L-Dopa as the stimuli), or <= 16 ng/mL [when growth hormone-releasing peptide 2 (GHRP-2) is the stimulus], determined with a validated assay. Subjects with organic brain disease, deficiency of a pituitary hormone other than GH or a documented history of symptomatic hypoglycemia may, if deemed appropriate by the Medical Monitor, qualify for inclusion with one GH stimulation test rather than two.
b. Diagnosis of at least one additional pituitary hormone deficiency
c. Congenital hypopituitarism due to congenital hypothalamic-pituitary defect (e.g., ectopic posterior pituitary, pituitary hypoplasia, abnormal stalk, septo-optic dyplasia) or genetic defect (e.g., GH1, POU1F1, or PROP1)
d. Impaired height
(1) Defined as at least 2.0 SDS below the mean HT for chronological age and sex (HT SDS <= -2.0) according to the Japanese year 2000 national growth survey reference data
(2) For subjects with HT SDS > -2.0, who have benign, organic, intracranial lesions (such as Rathke's cleft cyst) causing deficiency of at least one pituitary hormone in addition to GH, if
I. the growth velocity was <= 1.5 SD below the age-appropriate mean in the normal population over at least 6 months prior to diagnosis
II. and with appropriate documentation of growth velocity as confirmed by the medical monitor
e. IGF-1 level >= 1 SD below the mean IGF-1 level standardized for age and sex according to the reference values of the laboratory that measured the IGF-1.
f. Bone age x-ray > 6 months less than chronological age
2) 3 to 16 years old for boys and girls, inclusive, at Visit 1
3) Subjects who are prescribed daily hGH at a dose of >= 0.175 mg hGH/kg/week for at least 13 weeks but no more than 130 weeks prior to Visit 1
4) Tanner stage < 5 at Visit 1
5) Open epiphyses (bone age <= 14.0 years for females or <= 16.0 years for males)
6) Written, signed, informed consent of the parent or legally acceptable representatives of the subject and written assent of the subject as required by the IRB/IEC.

Exclude criteria

Main period
<Treatment naive subjects>
1) Children with a weight below 5.5 kg
2) Prior exposure to recombinant hGH or IGF-1 therapy
3) Children with a history of benign intracranial tumors unless there is documentation(within 6 Month(M) prior to Screening)to confirm no growth within the past 2 years. Children with non-malignant meningiomas are not eligible
4) Children born small for gestational age(i.e., birth weight <= -2.0 SD for gestational age, with or without a birth length < -2.0 SD for gestational age)
5) Malnutrition, defined as:
- Serum albumin level below the lower limit of normal(LLN)according to the reference ranges of the central laboratory, and
- Serum iron below the LLN according to the reference ranges of the central laboratory, and
- BMI <= -2.0 SD for age and sex
6) Children with psychosocial dwarfism
7) Children with idiopathic short stature
8) Other causes of short stature such as coeliac disease(confirmed by anti-transglutaminase antibodies test), hypothyroidism, or rickets
9) History or presence of malignant disease; any evidence of present tumor growth; children with GHD and clinically cured tumors may be eligible after consultation with the Medical Monitor(MM)
10) Any clinically significant abnormality likely to affect growth or the ability to evaluate growth with standing height measurement(e.g., chronic diseases like renal insufficiency, spinal cord irradiation or significant spinal abnormalities including but not limited to spina bifida variants or significant kyphosis or scoliosis)
11) Subjects with poorly controlled diabetes mellitus(DM) (HbA1c >= 8.0%)or diabetic complications
12) Known chromosomal abnormalities and other named medical syndromes known to impact growth(e.g., Turner syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions and skeletal dysplasias)with the exception of septo optic dysplasia
13) Closed epiphyses
14) Tanner stage > 1 (scant pubic hair alone does not exclude the subject)
15) Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids and including methylphenidate and other stimulant medications used for ADHD. With the exception of hormone replacement therapies(e.g., levothyroxine or hydrocortisone when used for hormone replacement). Medication for ADHD will be allowed for subjects to start after enrollment. Glucocorticoids not given for hormone replacement therapy are discussed separately below.
16) Children requiring systemic glucocorticoids for reasons other than as hormone replacement therapy, inhaled, or mid- to high-potency topical glucocorticoids as follows:
A. Children requiring inhaled glucocorticoid therapy(e.g., asthma)who used a dose of greater than 400 microgram/d of inhaled budesonide or equivalent for more than 28 days cumulatively over the course of the 12M prior to screening(or who will likely require treatment with more than 400 microgram/d of inhaled budesonide or equivalent for more than 28 days cumulatively in a calendar year during the trial). Chronic use of lower doses of inhaled glucocorticoids is not a reason for exclusion.
(Note: Approximately equivalent doses to budesonide DPI 400 microgram/d: beclomethasone[HFA; extra fine particles], 240 microgram/d; beclomethasone[HFA, standard particles], 400 microgram/day; ciclesonide[HFA], 240 microgram/d; flunisolide[HFA], 240 microgram/d; fluticasone propionate[HFA], 220 microgram/d; fluticasone propionate[DPI], 250 microgram/day; mometasone[DPI], 220 microgram/d; triamcinolone[CFC], 900 microgram/d; [HFA, CFC=metered dose inhaler with hydrofluoroalkane or chlorofluorocarbon propellant; DPI=dry powder inhaler)
B. Anticipated use of systemic glucocorticoids for reasons other than as hormone replacement therapy, or mid- to high-potency topical glucocorticoids(e.g., for allergic/atopic or inflammatory conditions)for more than 28 days cumulatively in a calendar year during the first year of the trial. This limitation, however, does not apply to topical steroids in the lowest potency group such as hydrocortisone, or others of equivalent potency.
17) Major medical conditions and/or presence of contraindication to hGH treatment except well-controlled DM
18) Known or suspected human immunodeficiency virus(HIV)-positive subject
19) Known hypersensitivity to the components of the study drug
20) The subjects and/or the parents/legally acceptable representatives are likely to be non-compliant with respect to trial conduct
21) Participation in any other trial of an investigational agent within 3M prior to Screening
22) Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule
Extension period
1) Poorly-controlled DM(HbA1c >= 8.0%)or diabetic complications
2) Evidence of closed epiphyses, defined as bone age > 14.0 years for females or > 16.0 years for males
3) Major medical conditions unless deemed appropriate by MM
4) Known hypersensitivity to the components of the trial medication
5) Likely to be non-compliant with respect to trial conduct(in regard to the subject and/or the parent/legally acceptable representatives)
6) Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule
7) Pregnancy
8) Sexually active subjects unwilling to use contraceptive methods during the trial and for 2 weeks after the last dose of lonapegsomatropin
<Treatment experienced subjects>
1) Weight of < 5.5 kg or > 80 kg at Screening
2) Females of child-bearing potential(until non-clinical developmental toxicity studies have been completed and confirm participation by females of child-bearing potential to be acceptable)
3) Male subjects who are sexually active must use a condom, or his female partner of childbearing potential must use an effective form of contraception, from the beginning of screening to the last trial visit.
4) History of malignant disease
5) Any clinically significant abnormality likely to affect growth or the ability to evaluate growth(e.g., chronic diseases or conditions such as renal insufficiency, spinal cord irradiation, hypothyroidism, active celiac disease, malnutrition or psychosocial dwarfism)
6) Poorly-controlled DM(HbA1c > 8.0%)or diabetic complications
7) Known neutralizing antibodies against hGH
8) Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids or oral glucocorticoids and including methylphenidate and other stimulant medications used for ADHD, with the exception of hormone replacement therapies for hypopituitarism: hypothyroidism(thyroxine), adrenal insufficiency(hydrocortisone), hypogonadism(sex steroids), diabetes insipidus(desmopressin).
9) Requiring inhaled glucocorticoid therapy(e.g., asthma) at doses higher than 400 microgram/d of inhaled budesonide or equivalent for longer than 3M during the 12M prior to Visit(V)1
10) Concomitant administration of one of the following:
- Chronic oral glucocorticoids used for more than 3M of the 12M prior to V1, other than as replacement therapy for congenital hypopituitarism
- Weight-reducing drugs or appetite suppressants
11) Major medical conditions, unless deemed appropriate by MM
12) Pregnancy
13) Presence of contraindications to hGH treatment
14) Known or suspected HIV-positive status
15) Known hypersensitivity to the components of the trial medication
16) Likely to be non-compliant with respect to trial conduct(in regards to the subject and/or the parent/legally acceptable representatives)
17) Participation in any other trial of an investigational agent within 30 days prior to V1
18) Prior exposure to investigational hGH
19) Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule

Related Information

• Primary Sponsor: Beckert Michael