| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Growth hormone deficiency |
|
| E.1.1.1 | Medical condition in easily understood language |
| Growth hormone deficiency |
|
| 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 | 20.0 |
| 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 |
|
| 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 |
| Preliminary clinical validation of predictive enrichment marker (PEM) strategy intended to select subjects likely to respond to therapy with LUM-201 based upon the percentage of subjects defined as PEM test positive (GH ≥ 5 ng/mL and baseline insulin-like growth factor 1 [IGF-1] > 30 ng/mL [> 3.92 nmol/L]) who have a positive growth response (“responders”) defined as ≥ 6.85 cm/yr annualized height velocity (AHV) from Baseline (Day 1) to Month 6. |
|
| E.2.2 | Secondary objectives of the trial |
Select a pediatric dose of LUM-201 for use in future studies including Phase 3 trial(s) based on comparison of 6-month, AHVs achieved by daily rhGH and the dose levels of LUM-201 treatment in subjects with pediatric growth hormone deficiency selected by predictive enrichment markers (PEMs)
Assess the safety and tolerability of oral LUM-201
Assess the reproducibility of the PEM positive classification of subjects
Assess additional clinical parameters of efficacy including change in height standard deviation score (HT-SDS) from Day 1 to Month 6, change in weight and weight SDS, change in body mass index and BMI SDS, change in Bone Age, change in predictive adult height
Further explore pharmacokinetics of LUM-201 based upon plasma LUM-201 concentrations
Determine short- and long-term pharmacodynamic (GH, IGF-1, IGFBP-3) responses to daily LUM-201
Characterize variance in AHVs of rhGH and LUM-201 to enable sample size estimates for future trials |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have an established diagnosis of idiopathic PGHD made prior to screening for entry into this study. This diagnosis is to be made in standard of care fashion incorporating biochemical, radiographic and auxological data. Specific inclusion criteria listed in this section for inclusion into this study protocol which are also used to diagnose PGHD in general are not intended to replace, supplant, or be an all-inclusive substitute for a standard of care diagnosis. Eligible subjects must be naïve-to-treatment and be prepubertal.
2. The diagnostic workup must include a maximal GH response < 10 ng/mL from two prior GH stimulation tests within the past 12 months (eligible tests include: glucagon, insulin, arginine, clonidine, and L-DOPA, exercise, and overnight sampling), or a single combined GH stimulation test using clonidine and arginine.
3. At the Screening visit or in the prior 12 months have a morning or random cortisol ≥ 7 μg/dL (193 nmol/L). Subjects with morning or random cortisol response < 7 μg /dL require a stimulated cortisol test (ACTH, insulin, glucagon) to be eligible for the study. Stimulated cortisol response should be ≥ 14 μg /dL (386 nmol/L).
4. Be willing to provide written informed consent (and assent where applicable) to participate in this trial.
5. At the Screening visit, be age ≥ 3.0 years and age ≤ 11.0 years for girls and ≤ 12.0 years for boys.
6. Have HT-SDS ≤ -2.0 or a HT-SDS ≥ 2 SD below MPH HT-SDS. If the other data (slow HV, low IGF-1, peak GH < 10, and 6-month BA delay) are all consistent with idiopathic GHD, the subject may be enrolled with a height SDS > -2.0 after consultation with the MMs. The use of National Growth Charts to compute HT-SDS is permitted for ex-US sites.
7. Have a baseline height velocity ≤ 5.5 cm/year based on at least 6-months of growth.
8. Have a BA examination at Screening or within the 9 months prior to Screening that is delayed by ≥ 6 months with respect to chronological age. BA should be based on the apparent BA of the proximal and distal phalanges, as opposed to the metacarpals, carpals and distal forearm. A central BA reader will make the final determination on BA eligibility.
9. Have prepubertal status as evidenced by Tanner Stage I breast development in girls and testicular volume < 4.0 mL in boys.
10. Have an arm span to height ratio > 96.5%.
11. In girls, have genetic testing results to rule out Turner syndrome. If SHOX genetic testing results are available, they need to be negative.
12. Have normal thyroid function. Subjects diagnosed with hypothyroidism must have documented successful treatment for at least 30 days prior to Day 1.
13. Baseline IGF-1 concentration > 30 ng/mL (> 3.92 nmol/L) and a peak GH response of ≥ 5 ng/mL from the Screening LUM-201 stimulation PEM test.
14. Subjects who are sexually active must use an acceptable form of contraception. |
|
| E.4 | Principal exclusion criteria |
1. Any medical or genetic condition which, in the opinion of the Investigator or MM, can be an independent cause of short stature and/or limit the response to exogenous growth factor treatment. (Examples: diabetes, idiopathic short stature (ISS), SHOX-deficiency, any chondrodysplasia, constitutional growth delay, SGA, other named syndromes).
2. A medical or genetic condition that, in the opinion of the Investigator and/or MM, adds unwarranted risk to use of LUM-201 or rhGH.
3. Use of any medication that, in the opinion of the Investigator and/or MM, can independently cause short stature or limit the response to exogenous growth factors (Example: glucocorticoids).
4. The presence of any circumstance likely to prevent successful completion of this trial.
5. Evidence or history of an intracranial mass (e.g., pituitary tumor, craniopharyngioma).
6. Prior treatment with growth factors including, but not limited to, GH, IGF-1, and GH secretagogues. (These may be used for limited times as a diagnostic test).
7. Suspicion of absent pituitary function as evidenced by a maximal stimulated GH ≤ 3 ng/mL on two prior standard of care GH stimulation tests, or pituitary deficiencies beyond GH and thyroid function, or a diagnosis of organic PGHD. Note: if a maximal stimulated GH response is > 3 ng/mL on one of the prior standard of care GH stimulation tests, subject is potentially eligible for participation in the study.
8. Malnutrition as evidenced by medical history or a BMI < 5th percentile.
9. BMI > 95th percentile.
10. Gestational age-adjusted birth weight < 3rd percentile (small for gestational age).
11. Participation in any therapeutic trial of investigational drug(s) within the prior 6 months.
12. Known or suspected allergy to LUM-201, rhGH or one of their excipients.
13. Unwilling to accept randomization assignment.
14. Treatment with medications known to be moderate or strong inhibitors or strong inducers of CYP3A/4.
15. Treatment with medications known to be predominantly metabolized (< 5% contribution by other isoforms) by either CYP3A/4, CYP2C8, CYP2C9 or CYP2C19.
16. Treatment with medications known to act as strong inhibitors of P-glycoprotein (P-gp) or potent substrates of P-gp or Multidrug and toxin extrusion protein 1 (MATE1).
17. History of spinal, cranial, or total body irradiation.
18. Recent commencement (within three months of the Screening visit) of non-stimulant therapy to treat attention deficit hyperactivity disorder (ADHD). MM should be contacted prior to screening of any potential subjects diagnosed with ADHD. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Preliminary clinical validation of predictive enrichment marker (PEM) strategy intended to select subjects likely to respond to therapy with LUM-201 based upon the percentage of subjects defined as PEM test positive (GH ≥ 5 ng/mL and IGF-1 > 30 ng/mL [> 3.92 nmol/L]) who have a positive growth response (“responders”) defined as ≥ 6.85 cm/yr AHV from Baseline (Day 1) to Month 6. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Assessment of reproducibility of the PEM positive classification.
Selection of a pediatric dose of LUM-201 for use in future studies including Phase 3 trial(s) based on comparison of 6-month, AHVs achieved by daily rhGH and the dose levels of LUM-201 treatment in subjects with PGHD selected by PEMs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| 3 different strenghts of LUM-201 compared with rhGH |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Israel |
| New Zealand |
| United States |
| Russian Federation |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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