| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Diabetic Macular Edema (DME) in hypertensive patients | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10057915 | | E.1.2 | Term | Diabetic macular oedema | | 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 assess the effect of aliskiren compared to placebo on change in central retina thickness (CRT), measured by
optical coherence tomography (OCT), from the baseline thickness in patients with type 1 or type 2 diabetes, after
12 weeks of treatment. | |
| E.2.2 | Secondary objectives of the trial | To assess the effect of aliskiren on BCVA in terms of change from baseline in no. of letters correctly identified at
12 weeks;-on BCVA in terms of the proportion of patients with a ≥ 15 letter gain or loss on BCVA at 12 weeks
from baseline.
To investigate relationship between change in macular edema and change in the RAS and angiogenic biomarkers.
To assess effect of aliskiren on the percent of change in central retina thickness measured by optical coherence
tomography from the baseline thickness that is above the lower limit of normal retina thickness in patients with
type 1 or type 2 diabetes, after 12 weeks of treatment.
To assess effect of aliskiren on change from baseline in central retinal thickness in terms of the proportion of
patients with a ≥ 75 micron decrease in CRT or a return to normal CRT, defined as no evidence of DME on OCT
and a CRT of ≤ 245 microns at 12 weeks from baseline. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Male and female patients age 18 to 85 years of age inclusive, with type 1 or type 2 diabetes that is actively
managed by a physician with hemoglobin A1C that is < or = to 10 (at screening).
2.Macular edema with average retinal thickness measured at the central subfield (by OCT) to be ≥ 280 um.
3.Ocular media and pupil dilation sufficient to allow fundus photography.
4.In the judgment of the study ophthalmologist, it is safe to withhold treatment of either eye with laser
photocoagulation, intra-vitreal steroid injection, or intra-vitreal VEGF inhibitor for the duration of the study.
5.At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed
in the sitting position after the patient has rested for at least three (3) minutes. Vital signs should be within the
following ranges:
body temperature between 35.0-37.5 °C
systolic blood pressure, 90-150 mm Hg
diastolic blood pressure, 50-95 mm Hg
pulse rate, 40 - 90 bpm | |
| E.4 | Principal exclusion criteria | 1. Macular atrophy/scarring/fibrosis, or exudates in the study eye that would preclude
improvement in visual acuity.
2. Media opacity in the study eye of sufficient severity to interfere with detection of a 3 line
improvement in acuity compared to baseline.
3. Any progressive disease of the retina (e.g. uveitis, rod-cone dystrophy) or optic nerve (e.g.
glaucoma) other than diabetic retinopathy.
4. Proliferative diabetic retinopathy or severe preproliferative diabetic retinopathy in the
study eye that should, in the opinion of the investigator, be treated by photocoagulation
within 16 weeks of the screening visit.
5. Intra-ocular pressure > 25 mmHg (Goldman applanation) in either eye at screening.
6. Best corrected visual acuity worse than 20/320 in the study eye at screening or baseline.
7. Prior intra-ocular surgery in the study eye with the exception of uncomplicated cataract
extraction more than 6 months prior to screening.
8. Laser photocoagulation in the study eye within three months prior to baseline.
9. Previous treatment with an intra-vitreal VEGF inhibitor or an intra-vitreal corticosteroid in
the study eye within 6 months prior to screening.
10. Treatment with a topical or oral carbonic-anhydrase inhibitor within one month prior to
baseline.
11. Current use of or likely need for systemic medications known to be toxic to the lens,
retina, or optic nerve (e.g., deferoxamine, hydrochloroquine, ethambutaol).
12. Patients with estimated glomerular filtration rate (GFR) < 50 ml/min (MDRD formula) at
screening.
13. Plasma/serum potassium > 5.0 mmol/L at screening.
14. Any episodes of clinically significant hypoglycemia requiring medical intervention/
hospitalization within 3 months prior to screening.
15. 2 or more episodes of ketoacidosis within one year of screening. Patients with the latest
episode of ketoacidosis within 3 months of screening will be excluded.
16. For normotensive patients, any history of clinically significant hypotension requiring
medical attention within 12 months prior to screening.
17. Patients with heart failure NYHA class II-IV.
18. History of myocardial infarction, coronary bypass surgery, or any percutaneous coronary
intervention (PCI) within 6 months prior to screening.
19. Second or third degree heart block without a pacemaker.
Novartis Confidential Page 31
Protocol Amendment No. 4 Protocol No. CSPP100A2244
20. History or presence of cardiac arrhythmia within 6 months prior to screening that required
antiarrhythmic drugs therapy.
21. Clinically significant valvular heart disease
22. Stroke within the 12 months prior to screening.
23. History of drug allergy or intolerance to aliskiren.
24. History of angioedema from ACE inhibitors, ARBs, or aliskiren therapy.
25. Patients with clinically significant thyroid dysfunction not controlled by any medications. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | change in central retina thickness from baseline thickness in patients with hypertension and type 1 and 2 diabetes
after 12 weeks treatment
change on BCVA - change from baseline in no of letters; with a ≥ 15 letter gain or loss on the BCVA at 12 weeks
from baseline | |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| 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.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | Study termination: 12 week treatment duration to detect possible therapeutic effect of aliskiren
The study will be terminated if an unexpectedly high rate of adverse effects on renal function, blood pressure, or
diabetic retinopathy is observed in study patients | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
