| 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 | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057934 |
| E.1.2 | Term | Diabetic macular edema |
| E.1.2 | System Organ Class | 100000004853 |
|
| 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 demonstrate that CT-P42 is similar to Eylea in terms of efficacy as determined by clinical response according to the mean change from baseline at Week 8 in Best Corrected Visual Acuity (BCVA) using Early Treatment of Diabetic Retinopathy Study (ETDRS) chart |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate additional efficacy, pharmacokinetics (PK), usability, and overall safety including immunogenicity |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1. Male or female patient aged ≥18 years.
2. Patient who has type 1 or 2 DM.
3. Patient with DME secondary to DM involving the center of the macula (defined as the Optical Coherence Tomography [OCT] central subfield) in the study eye.
4. Patient whose central subfield retinal thickness is ≥350 µm as assessed by OCT based on central results in the study eye at Screening.
5. Patient who has BCVA score of 73 to 34 (approximate Snellen equivalent of 20/40 to 20/200) using ETDRS charts in the study eye at Screening and Day 1 (for more detailed BCVA procedures, see the study procedure manual).
6. Decrease in vision determined to be primarily the result of DME in the study eye.
7. Patient and/or their legally authorized representative are informed and will be given ample time and opportunity to read and/or understand the nature and purpose of this study including possible risks and side effects and must sign the informed consent form (ICF) before any specific procedures.
8. Female patient must agree to use highly effective methods of contraception consistent with local regulations during the course of the study and for at least 3 months following discontinuation of study drug (excluding women who are not of childbearing potential). Examples include the following:
a) Combined (estrogen and progestogen containing) or progestogen-only hormonal contraceptives associated with inhibition of ovulation
b) Intrauterine device or intrauterine hormone-releasing system
c) True abstinence, when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational drug, and withdrawal are not acceptable methods of contraception.
A woman is considered of childbearing potential, following menarche
and until becoming post-menopausal unless surgically sterile. Menopausal female patients must have experienced their last period more than 1 year prior to the date of informed consent to be classified as not of childbearing potential. Male patient who is sexually active with a woman of childbearing potential must agree to use highly effective method described as above or 2 acceptable methods of contraception (e.g., Male or female condom AND additional hormonal or barrier contraceptive method other than condom by female partner) consistent with local regulations during the course of the study and for at least 3 months following discontinuation of study drug. Contraception is not required if either patient or his/her partner who has been surgically sterilized more than 24 weeks prior to the date of informed consent. |
|
| E.4 | Principal exclusion criteria |
A patient meeting any of the following criteria are not eligible for inclusion in this study:
1. Patient who has only one functional eye, even if the eye met all other study requirements, or has and/or is likely to have amblyopia, amaurosis or ocular disorder with BCVA < 34 ETDRS letter score (approximate Snellen equivalent of < 20/200) in the fellow eye
2. Patient who currently has, or has a history (where indicated) of ocular condition including one or more of the following in the study eye:
a) Active proliferative diabetic retinopathy, or pre-retinal fibrosis involving the macula
b) Aphakia
c) Vitreomacular traction or epiretinal membrane that is expected to affect central vision
d) Iris neovascularization, vitreous hemorrhage, or tractional retinal detachment
e) Ocular inflammation (including trace or above)
f) Uncontrolled glaucoma or filtration surgery for glaucoma in the past or likely to be needed in the future
g) Intraocular pressure (IOP) ≥25 mmHg
h) Spherical equivalent of the refractive error of worse than -6 diopters myopia
i) Structural damage to the center of the macula that is likely to preclude improvement in BCVA following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard exudates
j) Concurrent and/or history of disease, other than DME, that could compromise visual acuity, require medical or surgical intervention during the study period, or could confound interpretation of the results (including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause) as assessed by the investigator
k) Inability to obtain fundus and OCT images due to, but not limited to, insufficient media clarity or inadequate pupil dilation
3. Patient who currently has, or has a history (where indicated) of ocular condition including one or more of the following in either eye:
a) Concurrent and/or history of idiopathic or autoimmune uveitis
b) Evidence or suspicion of infection including blepharitis, keratitis, scleritis, or conjunctivitis.
However, a patient who has completely recovered from the infection at Day 1 is allowed to be enrolled at the investigator’s discretion.
4. Patient who currently has, or has a history of (where indicated) systemic condition including one or more of the following:
a) Uncontrolled DM as defined by hemoglobin A1c >10%
b) Uncontrolled blood pressure defined as systolic ≥160 mmHg or diastolic ≥100 mmHg measured after 5 minutes of rest while sitting
c) History of vascular disease such as cerebrovascular accident, myocardial infarction, transient ischemic attack, or thromboembolic reaction including pulmonary embolism within 180 days prior to the first study drug administration
d) New York Heart Association Functional Classification Class III or IV heart failure, or severe uncontrolled cardiac disease (i.e., unstable angina)
e) Current treatment for serious systemic infection
f) History of recurrent significant infections in the opinion of the investigator
g) Renal failure requiring dialysis or renal transplant
h) History of malignancies within 5 years prior to the first study drug administration, except adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma in situ
i) History of other disease, metabolic dysfunction, physical examination finding, electrocardiogram (ECG) finding or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the investigator, contraindicates the use of the study drug or that might affect interpretation of the results of the study or render the patient at high risk for treatment complications
j) Evidence of significant uncontrolled concomitant diseases including cardiovascular system, nervous system, pulmonary, renal, hepatic, endocrine, gastrointestinal disorders, or psychiatric condition as assessed by the investigator.
For the complete list of exclusion criteria please refer to the study protoocol, section 4.1.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the mean change from baseline in BCVA using the ETDRS chart at Week 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The following secondary efficacy endpoints will be assessed at each applicable visit up to Week 52, Extension Week 0 and 4:
- Mean change in BCVA using the ETDRS chart from baseline;
- Proportion of patients who gained ≥ 5, ≥ 10, and ≥ 15 ETDRS letters from baseline in BCVA using the ETDRS chart;
- Proportion of patients who lost ≥ 5, ≥ 10, and ≥ 15 ETDRS letters from baseline in BCVA using the ETDRS chart;
- Mean change in central subfield thickness from baseline as determined
by spectral domain optical coherence tomography (SD-OCT);
- Percentage of patients with a ≥ 2-step improvement from baseline in the ETDRS DRSS score as assessed by fundus photography (FP)
The following secondary PK endpoints will be assessed:
- Maximum plasma concentration after the first study drug administration (Cmax1);
- Maximum plasma concentration after the fifth study drug administration (Cmax2);
- Time of observed maximum plasma concentration after the first study drug administration (Tmax1);
- Time of observed maximum plasma concentration after the fifth study drug administration (Tmax2);
The following secondary usability endpoint will be assessed:
- Number of injections with vial kit successfully administered by healthcare professionals at Week 0
- Number of injections with PFS successfully administered by healthcare professionals at Extension Week 0
The following secondary safety endpoints will be assessed:
- Incidence and severity of AEs (ocular and non ocular) including SAEs;
- Incidence and severity of adverse event of special interest (AESI);
- Intraocular pressure test, slit lamp examination, indirect
ophthalmoscopy, finger count/hand motion/light perception,
hypersensitivity monitoring, vital signs and weight measurement,
electrocardiogram (ECG), New York Heart Association (NYHA) Functional
Classification assessment, physical examination findings, pregnancy
testing, clinical laboratory analyses including hemoglobin A1c (HbA1c);
- Immunogenicity, as assessed by incidence of anti-drug antibody and
neutralizing antibody;
- Prior and concomitant treatments
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Efficacy endpoints at week 52, Extension Week 0 and 4
- Secondary PK and safety endpoints throughout the study
- Usability endpoint at Week 0 and Extension Week 0
|
|
| 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 | No |
| E.6.8 | Bioequivalence | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Usability and immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| PFS Extension Study is open label, one arm. Only the Main Study is controlled. |
|
| 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 | 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 | 6 |
| 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 |
| India |
| Korea, Republic of |
| Estonia |
| Latvia |
| Lithuania |
| Poland |
| Spain |
| Czechia |
| Germany |
| Hungary |
| Russian Federation |
| Slovakia |
| 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
|
| The end of the study is defined as the date of the final CSR generated. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 29 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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