E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Androgen-dependent non-metastatic prostate cancer and therapy-induced bone loss |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065687 |
E.1.2 | Term | Bone loss |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036910 |
E.1.2 | Term | Prostate cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To assess the effect of denosumab on lens opacification event development or progression by month 12 based on a change of ≥ 1.0 in posterior subcapsular (P), ≥ 1.0 in cortical (C), or ≥ 0.7 in nuclear opalescence (NO) using the Lens Opacities Classification System III (LOCS III) score. |
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E.2.2 | Secondary objectives of the trial |
• To assess the effect of denosumab on lens opacification event development or progression by month 12 based on a change of ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO using the LOCS III score
• To assess the effect of denosumab on lens opacification event development or progression by month 6 based on LOCS III scores
• To assess the effect of denosumab on confirmed lens opacification event development or progression by month 12 based on LOCS III scores
• To assess the effect of denosumab on the incidence of decreased best corrected visual acuity (BCVA) from the baseline BCVA on the ETDRS (“Early Treatment Diabetic Retinopathy Study”) charts
• To assess the effect of denosumab on change in refraction needed to achieve BCVA
• To describe the safety of denosumab administration as measured by adverse events and safety laboratory parameters |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Men ≥ 30 of age with non-metastatic prostate cancer
Have undergone bilateral orchiectomy or initiated ADT with GnRH agonists and is expected to continue on ADT for at least 12 months
ECOG score (0, 1, or 2)
Screening BCVA of 20/40, (6/12 or 0.5 on the decimal scale) or better using the ETDRS charts at 4 meters in one eye with a natural, intact lens
Bone Mineral Density (BMD) requirements:
• If < 70 years: BMD T-score at the lumbar spine, total hip, or femoral neck ≥ -2.5 and ≤ -1.0 (“osteopenia”; at least one site required).
• If ≥ 70 years: BMD T-score at lumbar spine and total hip and femoral neck ≥ -2.5
• At least 2 evaluable lumbar vertebrae
Signed informed consent |
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E.4 | Principal exclusion criteria |
Screening LOCS III grade in both eyes of ≥ 3.5 for P, ≥ 4.0 for C, or ≥ 4.5 for NO
Bone Mineral Density (BMD) T-score < -2.5 at lumbar spine and/or total hip and/or femoral neck (“osteoporosis”)
Known history of prior fragility fracture (fractures associated with no or minimal trauma severity [eg, fall from standing height])
Evidence of distant metastases
Diagnosis of any secondary non-prostate malignancy within 5 years of randomization, except for adequately treated basal cell or squamous cell skin cancer
Known HIV, HCV, or Hepatitis B Infection
Known osteonecrosis of the jaw (ONJ)
Current hyper-or hypothyroidism (stable on thyroid replacement therapy is allowed, if the TSH is within the normal range)
Paget’s disease, Cushing’s disease, hyperprolactinemia, chronic liver disease or rheumatoid arthritis
Dialysis or expected to undergo dialysis within 1 year
Unstable systemic disease including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before randomization
Major surgery, or significant traumatic injury occurring within 4 weeks before randomization
Incisional eye surgery in both eyes or cataract surgery in both eyes
Ocular disease leading to visual loss (eg, macular degeneration, glaucoma, corneal disease) that would make assessment of visual status difficult.
Planned cataract surgery or major visual disturbance expected to result in need for cataract surgery within one year
Concurrent systemic anti-neoplastic therapy or radiotherapy, other than ADT and/or anti-androgen therapy
Current administration of IV bisphosphonates (oral bisphosphonates allowable if they are stopped at study entry)
Concurrent use of anti-glaucoma medications
Concurrent chronic corticosteroid therapy or pulse corticosteroid therapy including ophthalmologic steroid use (topical, inhaled, or nasal steroids are allowed)
Maximal pupil dilation size <6.0 mm
Prior administration of denosumab
PSA > 5 ng/mL at screening
Serum calcium or albumin-adjusted serum calcium levels < 2.0 mmol/L (8.0 mg/dL), or ≥ 2.9 mmol/L (11.5 mg/dL)
25-hydroxyvitamin D deficiency (< 20 ng/mL)
Is currently enrolled in the active treatment phase of a study investigating an unapproved product or device, or has been treated within the last 30 days with an unapproved product or device. Subjects in the observational phase of clinical studies (eg, to collect survival data) are allowed
Organic or psychiatric disorder which, in the opinion of the investigator may prevent the subject from completing the study or interfere with the interpretation of the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
Subject incidence of lens opacification event development or progression by month 12, based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1-Subject incidence of lens opacification event development or progression by month 12, based on a change of ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III score
2-Subject incidence of lens opacification event development or progression by month 6, based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score
3- Subject incidence of confirmed lens opacification event development or progression by month 12, based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score. A confirmed lens opacification event development or progression is defined as two directly subsequent events per protocol assessments at the same location (P, C, NO) using LOC III as above.
4- Subject incidence of a decrease from baseline in BCVA as measured by a change of ≥ 10 letters on the ETDRS at 4 meters, at months 3, 6, 9, and 12
5- Change in refraction needed to achieve BCVA at 3, 6, 9, and 12 as measured by change in sphere
6- Adverse event incidence, serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- Month 12
2- Month 6
3- Month 12
4- Months 3, 6, 9, and 12
5- Months 3, 6, 9, and 12
6- Month 12
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 2 |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Canada |
European Union |
India |
Mexico |
New Zealand |
Russian Federation |
South Africa |
Ukraine |
United States |
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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
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End of study will occur when the last subject has completed their month 12 visit or has withdrawn from the study. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 |