E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Growth Hormone Deficiency in adults |
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E.1.1.1 | Medical condition in easily understood language |
Growth Hormone Deficiency, GHD |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10056438 |
E.1.2 | Term | Growth hormone deficiency |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To evaluate the safety of individualized dosing of Somavaratan for up to five months as assessed by review of the accumulated safety data in each treatment cohort
•To evaluate the starting doses of Somavaratan for each cohort as measured by the proportion of subjects who achieve normalization of IGF-I SDS response (reference range of -2.00 to 2.00 SDS) during the first dosing interval (one month after the first dose)
•To evaluate the dose titration plan of Somavaratan for each cohort as measured by the proportion of subjects who achieve a mean IGF-I SDS (based on pre-dose and 7 days after dosing values) within the defined target range of 0 to 1.50 after each dose titration
•To determine whether IGF-I response over the 30 day dosing interval can be determined by using the SDS of the mean of IGF-I values from pre-dose and 7 days after dosing
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E.2.2 | Secondary objectives of the trial |
•To evaluate the immunogenicity of Somavaratan by measurement of serum anti-drug antibody (ADA) titers and detection of neutralizing antibodies (NAb) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female or male subjects with age 23 to 70 years (inclusive).
2. Female subjects of childbearing potential must agree to use appropriate contraceptive methods during the study and continue this method for at least one month after their study completion.
3. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening.
4. Subjects must have a documented medical history of GHD during adulthood, according to established guidelines (confirmatory testing
should be done to document persistence of childhood onset GHD into adulthood if necessary). Acceptable diagnostic criteria include:
- insulin tolerance test (ITT): peak hGH ≤ 5.0 ng/mL
- arginine alone: peak hGH ≤ 1.4 ng/mL
- arginine + growth-hormone-releasing hormone
- glucagon stimulation test: peak hGH ≤ 3.0 ng/mL
OR
- at least 3 pituitary hormone deficiencies and a low IGF-I for age/gender
For arginine + GHRH stimulation test, peak hGH limit is based upon body mass index as follows: ≤ 11.0 ng/mL for BMI < 25 kg/m2; ≤ 8.0 ng/mL for 25 ≤ BMI < 30 kg/m2; ≤ 4.0 ng/mL for BMI ≥ 30 kg/m2.
Current height may be used to determine BMI if BMI is not available from the date of the stimulation test.
If documented confirmation is not available, GH stimulation test may be performed at Screening (subjects receiving daily rhGH therapy must be withdrawn for at least 7 days prior to testing).
5. Subjects taking other hormone replacement therapy for pituitary failure must have been on a stable course of treatment for at least 3 months prior to Screening.
6. Subjects with underlying disorders responsible for the subject's GHD must have been clinically stable for at least 6 months prior to Screening.
7. If a subject is currently receiving daily recombinant human growth hormone (rhGH) injections for treatment of GHD, must agree to stop taking prescribed daily rhGH therapy for the washout period of 14 days minimum.
8. Subjects must agree to inform the prescribing physician of study involvement, and the Investigator, prior to initiating a new medication (prescription or over-the-counter).
9. Subjects must provide signed informed consent.
10. Subjects must have a BMI (kg/m2) between 19.0 and 35.0 (inclusive).
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E.4 | Principal exclusion criteria |
1.Subjects with a documented history of diabetes mellitus or inadequate glucose control as defined by a historical or Screening value of:
•FPG > 126 mg/dL (7 mM), or
•HbA1c ≥ 6.5%
2.Subjects with untreated adrenal insufficiency. Adrenal insufficiency will be screened by morning serum cortisol followed by ACTH stimulation test for subjects without documented history of adrenal insufficiency.
3.Subjects with free thyroxine outside the normal reference range.
4.Subjects currently taking oral glucocorticoids, except for physiological maintenance doses of oral glucocorticoids in subjects with multiple pituitary hormone deficiencies.
5.Subjects with current significant cardiovascular disease, heart insufficiency of NYHA class > 2.
6.Subjects with current significant cerebrovascular, pulmonary, neurological (not considered related to GHD), renal, inflammatory, or hepatobiliary disease.
7.Subjects with current papilledema.
8.Subjects with a history of persistent (unresolved without medical intervention) or recurring migraines.
9.Subjects with current edema (≥ CTCAE Grade 2).
10.Subjects with current drug or alcohol abuse.
11.Subjects with a documented history of HIV, current HBV or HCV infection (testing not required).
12.Subjects with a prior history of malignancy or abnormal results of any routine cancer screening tests, excluding adequately treated non-melanoma skin cancers or adequately treated in situ carcinoma of the cervix.
13.Women who are pregnant or breastfeeding.
14.Subjects treated with an investigational drug within 30 days prior to Screening.
15.Subjects with a significant abnormality in Screening laboratory results as interpreted by the Investigator and/or the Medical Monitor.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. IGF-I SDS levels within therapeutic range after 1st dose
2. IGF-I SDS levels within target range following each dose
3. Compare mean IGF-I from 2 values vs mean IGF-I from 4 values
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Predose and Day 7 following 1st dose
2. Predose and Day 7 following each dose
3. Predose and Days 7, 21 and 30 following each dose
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E.5.2 | Secondary end point(s) |
1. Serum anti-drug antibody titers
2. Serum neutralising antibodies
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Prior to each dose and at end of study
2. Prior to each dose and at end of study
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Germany |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial will be last visit of last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |