| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
| 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 | 10031282 |
| E.1.2 | Term | Osteoporosis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Additional details were added regarding what is being examined in the hand film to assess whether patients have radiographic evidence of closed epiphyses.
To assess the safety and abilty for the body to tolerate a single dose of the study drug, odanacatib in 12-25 year olds.
This study also aims to look at the levels of certain parameters that are associated with how the study drug acts in the body (pharmacokinetic parameters). The levels of these parameters will be measured in the blood following a single oral dose of the study drug. This will then be compared between the groups of participants. |
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| E.2.2 | Secondary objectives of the trial |
To assess the effects of single oral dose of diffrent doses of the study drug, Odanacatib, on the levels of a chemical marker of the break down of bone structure (bone resorption) in the urine of in mature adolescents receiving glucocorticoids.
To evaluate the relationships between what the human body does to the study drug and what the study drug does to the human body by assesing the concentration and inhibition of the chemical marker of the break down of bone structure (bone resorption).
To use the data generated by this study to predict an appropriate dose in mature adolescents if neither 10 mg nor 50 mg demonstrates similarity of total amount of drug absorbed by the body in adult controls. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Updated criteria to allow use of appropriate
double barrier contraception as per local regulations or guidelines.
Updated criteria to allow patients to be included if they take on the order of 5 mg/day prednisone or equivalent, but they can also exceed 5 mg/day of prednisone or equivalent
Consent/Assent for Panels A and B only:
1. The parent or guardian and subject agree to the subject’s participation in the study as indicated by parental/guardian signature on the consent form and subject assent. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
Written assent will be sought from subjects of appropriate intellectual maturity. The subject is willing to comply with procedures, and is able to keep scheduled clinic visits.
Or
Consent for Panel C only:
1. The subject is willing to give written informed consent to participate in the trial.
2. The subject is a male or female between the ages of 12 and 17 years of age (inclusive) on the day of screening for Panels A and B only. The subject is a male or female between the ages of 18-25 years of age (inclusive) on the day of screening for Panel C only.
3. Female subjects of reproductive potential (or other female subjects at the discretion of the investigator) must demonstrate a serum or urine β-hCG level consistent with the nongravid state at the prestudy (screening) visit and agree to use (and/or have their partner use) two (2) acceptable methods of birth control beginning at the prestudy (screening) visit throughout the study and until 2 weeks after administration of study drug. Acceptable methods of birth control are as follows. Females of childbearing potential can be enrolled. However, two (2)
acceptable methods of barrier contraception must be used beginning at
the prestudy visit, throughout the study and until 2 weeks after the dose
of study drug. Acceptable methods of birth control are two (2) of the following: intrauterine device (IUD without local hormone release), diaphragm, spermicides, cervical cap, contraceptive sponge, and /or condoms. Abstinence is an alternative life style and subjects practicing abstinence may be included in the study.
Alternatively, women may use an appropriate hormonal contraception instead of one of
the two barrier methods. Appropriate hormonal contraception may include any marketed
contraceptive agent that contains an estrogen and/or a progestational agent (including
oral, subcutaneous, transdermal, intrauterine, or intramuscular agents). If hormonal
contraception is used as one of the methods, hormonal contraceptives must have been
used for at least 2 months prior to administration of trial drug for subjects to be eligible
for enrollment into the trial.
4. Subject is currently receiving glucocorticoid therapy and will be at a dose anticipated to be stable over the course of the study period starting
1 week prior to Day 1, through the poststudy visit. Subject must have started glucocorticoid therapy at least approximately 1 month prior to study drug administration. The dose of glucocorticoids should be ≥ 4.5
mg/day of prednisone or equivalent, other glucocorticoids may be allowable at the discretion of the investigator after consultation with the SPONSOR medical monitor.
Updated criteria ‘d’ to allow patients to be included if they take on the order of 5 mg/day prednisone or equivalent, but they can also exceed 5 mg/day of prednisone or equivalent
5. Subject (Panels A and B; Panel C at the discretion of the investigator and Sponsor) has radiographic evidence of closed epiphyses at the hand
as confirmed by an independent reviewer (i.e., central vendor).
6. Subject is willing to comply with the study restrictions (see Section 3.2 for a complete summary of study restrictions). |
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| E.4 | Principal exclusion criteria |
Updated criteria ‘d’ to allow for investigators to calculate creatinine clearance for Panels A and B by using either the Schwartz equation OR the Cockcroft-Gault Equation. Modified exclusion criteria to make it clearer that oral contraceptives are allowed if they patients started taking them 6 months prior to screening, though they still cannot be used as a method of birth control. Updated exclusion criterion ‘m3’ and ‘o’ to reduce the restriction for the length of time patients are required to be on a stable dose of thyroid hormone (levothyroxine, L-T4) from 3 months before dosing to 1 month before dosing, if they have a history/evidence of hypothyroidism and are euthyroid. 1. Subject or parent/legal guardian, is, in the opinion of the investigator, mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 years. Subjects who have had situational depression may be enrolled in the study at the discretion of the investigator.2. Female subject has a positive pregnancy test within 24 hours of study drug administration or an unwillingness to undergo pregnancy testing. 3. Subject has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
4. For Panels A and B only, subject has an estimated creatinine clearance of ≤ 80 mL/min based on the Schwartz equation; the Schwartz equation is:
CrCl (mL/min) = [length (cm) × k]/SCr (mg/dL)
where k = 0.55 for females age 12 to 17 years, and k = 0.7 for males age 12 to 17 years.
An actual creatinine clearance, as determined by a 24-hour urine collection, may be used in place of, or in conjunction with, the Schwartz equation. For Panel C only, subject has an estimated creatinine clearance of ≤80 mL/min based on the Cockcroft-Gault equation; the Cockcroft-Gault equation is:
ClCr = (140-age[yr])(body wt [kg])
(72)(serum creat [mg/dL])
When creatinine is measured in micromole/litre, use the following formula:
ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
An actual creatinine clearance, as determined by a 24-hour urine collection, may be used in place of, or in conjunction with, the Cockcroft-Gault equation; subjects who have an actual or estimated creatinine clearance up to 10% below 80 mL/min may be enrolled in the study at the discretion of the investigator. 5.Subject’s blood pressure is >95th percentile for age and gender (see Attachment 3: Pediatrics, Vol. 98, No. 4; 1996). Subjects with transient/intermittent blood pressure readings >95th percentile for age and gender may be enrolled at the discretion of the investigator.6. Subject has a history of malignant neoplastic disease. 7. Subject is a nursing mother.8. Subject has a serum calcium level obtained at screening that is below the lower limit of normal. 9. The subject has any clinically significant primary growth disorder (e.g., achondroplasiaor growth hormone deficiency). 10. The subject has any disease affecting the stomach or proximal small intestine resulting in malabsorption. 11. Prior to screening the subject received treatment which might have influenced bone turnover, including: a)Within 6 months of screening: anabolic steroids (including DHEA and other weaker analogs), testosterone, calcitonin, calcitriol, alfacalcidol, excess vitamin A (>10,000 units/day) or excess vitamin D (>3000 units/day), or cyclosporine. b)Within 3 weeks of screening, cyclosporine.
c)Thyroid hormone (levothyroxine, L-T4),However, if on a stable dose for at least 1 month before dosing, and has thyroid hormone parameters (TSH and/or T3 or FT4)within the reference range at screening, the subject may be allowed to participate after discussion with the SPONSOR medical monitor. d)Previous treatment with any marketed or experimental bisphosphonate within the 3 months preceding the screening visit.
l2.The subject has, within 3 years prior to screening, a history of, or evidence for, any clinically relevant metabolic bone disease (other than glucocorticoid-induced bone loss) including but not limited to primary hyperparathyroidism, hypoparathyroidism, hyperthyroidism, osteomalacia, and osteogenesis imperfecta.
13. The subject has a history of, or evidence for, hypothyroidism, unless the subject has been treated with a stable dose of thyroid hormone for at least 1 months prior to dosing, and has thyroid hormone parameters (TSH and/or T3 or FT4) within the reference range at screening. Subjects at screening discovered to have mild hypothyroidism (slightly elevated serum TSH) are eligible to enter the study provided they receive careful thyroid replacement therapy, if needed, and TSH and/or T3 or FT4 levels are monitored as appropriate during the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Number of Participants who Report an Adverse Event, Area under the concentration time curve from 0 hour to infinity(AUC0-∞), Area under the concentration time curve from 0 hour to 168hr of Odanacatib (AUC0-168hr), Maximum Plasma Concentration of odanacatib (Cmax), Plasma Concentration at 168hours (C168hr), Time to Cmax of odanacatib (Tmax), apparent terminal t1/2 of odanacatib |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| out to 14 days post dose(AEs); Hour 0 (predose) and at 1, 2, 6, 12, 24, 72, 120, 168, 240 and 336 hours post dose |
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| E.5.2 | Secondary end point(s) |
| Change from baseline in inhibition of urinary aminoterminal crosslinked telopeptide of Type 1 collagen (uNTx/Cr) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Modified Dose Administration and Postdose Procedures to reflect the changes made to the PK/PD sampling timepoints, deleting out the Day 1
72 hour and Day 1 120 hour postdose procedures and replacing them with the Day 1 96 hour postdose
procedure.
Modified Dose Administration and Postdose Procedures to reflect the need for patients to fast overnight prior to coming into the clinic for postdose procedures.
Updated blood volumes to reflect the changes to the PK/PD samplings.
Made modifications to the Urinalysis section to state that a dipstick is to be used as default, though if there are positive results on dipstick, that microscopies must be performed.
Corrected the size of the cryotube from 3.6 mL to 3.5 mL.
Added the note that serum and urine biomarker sample colle |
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration to paediatrics and PK/PD Study |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 9 |
| 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 |
| Italy |
| Korea, Republic of |
| Moldova, Republic of |
| United Kingdom |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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