| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Glaucoma, ocular hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Ocular Physiological Phenomena [G14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10018307 |
| E.1.2 | Term | Glaucoma and ocular hypertension |
| E.1.2 | System Organ Class | 10015919 - Eye disorders |
|
| 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 compare each combination of T4030 eye drops (unpreserved fixed combination of bimatoprost 0.01% and timolol 0.1% or 0.5%) with Ganfort® UD in terms of efficacy. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy, safety and blood concentration of each combination of T4030 versus Ganfort® UD. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| PK sub-study; Plasma concentrations of IP before instillation and 30 minutes, 1h, 1h30, 4h, 8h and 12h after instillation at Day 1 and Week 12 on a subgroup (around 30 patients); AUC (0-12h), Cmax, tmax, and t1/2. |
|
| E.3 | Principal inclusion criteria |
At Screening Visit:
1.1. Informed consent signed and dated
1.2. Patient aged ≥18 years old
1.3. 500 μm ≤ central corneal thickness ≤ 600 μm in both eyes
1.4. Both eyes with diagnosed open angle glaucoma or ocular
hypertension:
1.4.1 Initially treated and controlled for at least 6 months by dual
therapy of prostaglandin and timolol (fixed combination or not)
1.4.1.1. Both eyes with IOP ≤ 18 mmHg
1.4.1.2. History of IOP insufficiently controlled with first-line monotherapy based on the following reasons:
• No sufficient IOP reduction
Or
• Significant IOP reduction but progression of glaucoma (target IOP not reached)
1.4.1.3. Justification of an add-on IOP reduction with a combination of prostaglandin and timolol (fixed or not) 6 months after the switch from monotherapy to dual therapy (bitherapy)
OR
1.4.2 Initially treated with first-line monotherapy for at least 6 months, insufficiently controlled and requiring a dual therapy (bitherapy)
At Randomisation Visit (Day 1) at 9h00:
1.5. Both eyes with 22 mmHg ≤ IOP < 36 mmHg with asymmetry between eyes ≤ 3 mmHg |
|
| E.4 | Principal exclusion criteria |
Ophthalmic Exclusion Criteria in AT LEAST ONE EYE [2.1]
2.1.1 Funduscopy not performed or not available within 12 months
2.1.2 Visual field not performed or not available within 12 months
2.1.3 Advanced stage of glaucoma defined by at least one of the following criteria:
2.1.3.1 Absolute defect in the ten degrees central point of the visual field
2.1.3.2 Severe visual field loss : MD < -18 dB
2.1.3.3 Risk of visual field worsening as a consequence of participation in the study according to the investigator's best judgement
2.1.4 History of non-response to bimatoprost and/or timolol
2.1.5 Far Best Corrected Visual Acuity ≥ +0.7 LogMar (e.g., ≤0.2 in decimal value or ≤20/100 Snellen equivalent or ≤50 ETDRS letters)
2.1.6 History of trauma, infection, clinically significant inflammation within the 3 previous months
2.1.7 Ongoing or known history of ocular allergy and/or uveitis and/or viral infection
2.1.8 Clinically significant or progressive retinal disease (e.g. retinal degeneration, diabetic retinopathy, retinal detachment)
2.1.9 Presence of at least one severe objective sign among the following:
2.1.9.1 Conjunctival hyperaemia (Grade 5 / McMonnies scale)
2.1.9.2 Superficial punctate keratitis (Grade 4-5 / Oxford scale)
2.1.9.3 Blepharitis (Grade 3 / 0-3 scale)
2.1.10 Severe dry eye as assessed by the investigator
2.1.11 Corneal ulceration
2.1.12 Palpebral abnormalities incompatible with a good examination
2.1.13 Any other abnormality preventing accurate assessment e.g. reliable tonometry measurement, visual field examination, fundus examination
Systemic/Non Ophthalmic Exclusion Criteria [2.2]
2.2.1 Uncontrolled diabetic patient
2.2.2 History of cardiac disorders (except controlled arterial hypertension)
2.2.3 Any ECG abnormalities considered clinically significant and/or contraindicating the prescription of Timolol (Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block, or any relevant abnormalities) according to centralised medical review
2.2.4 Heart rate <50 bpm and/or systolic arterial blood pressure ≤90 mmHg
2.2.5 History of bronchopulmonary disorders (e.g. asthma, chronic obstructive pulmonary disease)
2.2.6 Known or suspected hypersensitivity to one of the components of the investigational product, run in treatment (sulphonamides) or auxiliary product (fluorescein, oxybuprocaine hydrochloride)
2.2.7 History of or active relevant systemic condition incompatible with the study or likely to interfere with the study results or the patient safety according to investigator judgement
Specific Exclusion Criteria Regarding Childbearing Potential Women[2.3]
2.3.1 Pregnancy or breast feeding
2.3.2 Childbearing woman who is not using a reliable method of contraception (oral contraceptive, intra-uterine device, subcutaneous contraceptive implant, vaginal ring, patch, double-barrier – i.e. condom associated with spermicide) and is not surgically sterilised
Exclusion Criteria Related to General Conditions [2.4]
2.4.1. Alcohol addiction and heavy smoker according to the investigator's judgement.
2.4.2. Inability of patient to understand the study procedures or to give informed consent
2.4.3. Non-compliant patient (e.g. not willing to attend a visit; way of life interfering with compliance)
2.4.4. Participation in this study at the same time as another clinical study
2.4.5. Participation in this study within the 4 weeks after the end of a previous clinical study (or within 5 half-lives of the previously tested product if longer than 4 weeks)
2.4.6. Patient previously randomised in this study
2.4.7. Patient being institutionalised because of legal or regulatory order, inmate of psychiatric wards, prison or state institutions, or employee of the study sites or of the sponsor's company
2.4.8. Patient not covered by the government health care scheme of the country in which he/she is living (if applicable)
2.5. Exclusion criteria related to previous and concomitant treatments (medications/non-medicinal therapies/procedures)
2.5.1. Patient with previous, current or anticipated prohibited treatment (or prohibited modification of treatment regimen).
The prohibited treatments (or prohibited modifications of treatment regimen) and their periods of use prohibition are listed in the following
Table 1: Prohibited Treatments (Medications/non-Medicinal Therapies/Procedures) in either eye. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in IOP (measured with Goldmann tonometer) between Day 1 and Week 12 at 8h00 in the worse eye.
The worse eye is defined as the eligible eye with the highest IOP at the randomisation visit at 8h00. In case of no IOP difference between both eyes, the right eye will be considered. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At Screening Visit and Week 6, one IOP measurement should be performed at 8h00 (± 30 minutes). On Day 1, Week 12 or premature discontinuation, IOP should be measured at three time points (8h00, 10h00, and 16h00). IOP measurements should be done at the same hours (± 30 minutes) as Day 1, with morning measurements of IOP at least 2 hours apart, by the same investigator and using the same technique (Goldmann applanation tonometer) for all visits. |
|
| E.5.2 | Secondary end point(s) |
Change in IOP between Day1 and Week 12 at 10h00, 16h00 in the worse eye,
Change in IOP between Day1 and Week 12 at 8h00, 10h00 and 16h00 in the contralateral eye,
Change in IOP between Day1 and Week 6 at 8h00 in the worse eye and in the contralateral eye,
Efficacy assessed by the investigator on Week 6 and Week 12.
Safety Parameters:
• Assessment of the conjunctival hyperaemia on McMonnies scale in each eye
• Score of each ocular symptom throughout the day (irritation/burning, stinging, itching, tearing, eye dryness feeling, foreign body sensation)
• Score of each ocular symptom upon instillation (irritation/burning, stinging, itching, tearing, eye dryness feeling, foreign body sensation)
• Score of each ocular sign (blepharitis, eyelid oedema, iris hyperpigmentation, abnormal eyelashes aspect, folliculo-papillary
conjunctivitis) in each eye
• Corneal fluorescein staining according to Oxford grading scheme in each eye.
• Far Best Corrected Visual Acuity in each eye
• Automated visual field and Funduscopy
• Electrocardiogram (ECG)
• Clinical systemic examination (heart rate, blood pressure)
• Ocular tolerance assessed by the investigator
• Ocular tolerance assessed by the patient
• Ocular and systemic AE |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At Screening Visit and Week 6, one IOP measurement should be performed at 8h00 (± 30 minutes). On Day 1, Week 12 or premature discontinuation, IOP should be measured at three time points (8h00, 10h00, and 16h00). IOP measurements should be done at the same hours (± 30 minutes) as Day 1, with morning measurements of IOP at least 2 hours apart, by the same investigator and using the same technique (Goldmann applanation tonometer) for all visits. |
|
| 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 | No |
| 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 | No |
| E.8.1.3 | Single blind | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| 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 | |
| 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 | 2 |
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