A Phase IIa Dose-Ranging Study to Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetic Profile of Multiple Escalating Doses of Carboxyamidotriazole Orotate (CTO) in Patients with Neovascular Age Related Macular Degeneration (AMD)

Phase 2

• Conditions: eovascular Age Related Macular Degeneration; Neovascular Age Related Macular Degeneration; Eye - Diseases / disorders of the eye

• Registration Number: ACTRN12612001130853
• Lead Sponsor: Rashida Karmali

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2012-10-23
• Last Update Posted: 13 January 2020

Recruitment & Eligibility

• Status: ot yet recruiting
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

1.Subfoveal CNV due to AMD (i.e., predominately classic, minimally classic or occult no classic) as documented by fluorescein angiogram.
2.Men and women aged 50 years and over.
3.Total area of the lesion (including blood, neovascularization, and scar/atrophy) must be less than or equal to 5 disc areas (DA), of which at least 50% must be active CNV. Active CNV is defined as the neovascular component of the lesion as defined by the fluorescein angiogram.
4.Best corrected visual acuity (BCVA) in the study eye between 73 and 25 letters, inclusive using an Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart.
5.For subjects with minimally classic CNV or occult no classic CNV, one of the following must be documented.
Any documented deterioration in visual acuity (VA), OR,
Any documented central retina subfield thickness increase more than 50 µm over upper normal value on spectral domain OCT or STRATUS time-domain OCT.,
Any blood (excluding intravitreal haemorrhage) or any documented increase in intra-retinal cysts (IRC) or sub retinal fluid (SRF).
6.Clear ocular media and adequate pupillary dilatation to permit good quality stereo color fundus photography.
7.Intraocular pressure (IOP) of 21 mmHg or less in either eye
8.Normal electrocardiogram (ECG) or clinically non-significant changes.
9.Women must be using two forms of effective contraception, be postmenopausal for at least 12 months prior to trial entry, or surgically sterile. Women of child-bearing potential must complete a serum pregnancy test within 14 days prior to the first administration with a negative result. The two forms of effective contraception must be implemented during the trial and for at least 60 days following the last dose of test medication.
10.Adequate hematological function: hemoglobin equal to 10g/dL (6,2 mmol/L); platelet count equal to 130 x 109/L; white blood cell count (WBC) equal to 3.8 x 109/L. Subjects with results outside these ranges may be enrolled at the discretion of the Investigator and in consultation with Tactical Therapeutics.
11.Adequate renal function: serum creatinine equal to 190 µmol/L. (2.5 mg/dl) and blood urea nitrogen (BUN) below 20 mmol/l, Creatinine Clearance of more than 30 mL/min calculated using the Cockcroft and Gault formula. Subjects with results outside these ranges may be enrolled at the discretion of the Investigator and in consultation with Tactical Therapeutics.
12.Adequate liver function: serum bilirubin equal to 1.5 mg/dl, (25 µmol/l) gamma-glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase within 2 x upper limit of normal (ULN). Subjects with results outside these ranges may be enrolled at the discretion of the Investigator and in consultation with Tactical Therapeutics.
13.The subject must have a body mass index of equal to 19.0 and 35.0 kg/m², inclusive.
14.Availability of the subject for the entire study period and willingness to adhere to protocol requirements, as evidenced by a signed, written, Informed Consent Form.

Exclusion Criteria

1.Any prior treatment for neovascular AMD or any intravitreal treatment for any indication in the study eye within three months prior to the baseline visit, except oral supplements of vitamins and minerals OR any general treatment with Anti-vascular endothelial growth factor (VEGF) in the last six months.
2.Any current and ongoing treatment for AMD or any intravitreal treatment for any indication in the non-study eye within the last three months (if anti VEGF treatment is needed in the non study eye during the study period this will be permitted, however treatment should not have started before recruitment of the study eye).
3.Ocular hypertension unless controlled with monotherapy.
4.Advanced glaucoma with any peripheral visual field loss.
5.Presence of pigment epithelial tears or rips.
6.Clinical evidence of known definite idiopathic polypoidal choroidal vasculopathy (IPCV) and/or evidence on fluorescein angiography.
7.More than 25% of the total lesion size made up of scarring or atrophy. Subjects with subfoveal scar or subfoveal atrophy are excluded.
8.Presence of intraocular inflammation (= trace cell or flare), macular hole, epiretinal membrane, RVO, BRVO, CRAO or BRAO, vascular closure of retina veins and arteries, vitreous hemorrhage or aphakia (pseudophakia with or without an intact capsule is not an exclusion criteria).
9.Presence of idiopathic or autoimmune-associated uveitis in either eye.
10.Significant media opacities, including cataract, which might interfere with VA, assessment of toxicity, or stereo color fundus photography. Subjects should not be entered if there is likelihood that they will require cataract surgery in the study eye in the following year.
11.Presence of other causes of choroidal neovascularization, including pathologic myopia (spherical equivalent of -8 diopters or more negative, or axial length of 25 mm or more), the ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis.
12.Any intraocular surgery or thermal laser within three months of trial entry. Any prior laser in the macular region, regardless of indication.
13.History of any of serious eye trauma or the following procedures: Posterior vitrectomy, filtering surgery (e.g. trabeculectomy), glaucoma drainage device, corneal transplant, or retinal detachment.
14.Previous or concomitant therapy with intravitreous corticosteroids.
15.Known allergy to fluorescein.
16.Any systemic disease likely to interfere with the study schedule or the ability to attend for the length of the study.
17.Subjects who have received any investigational drug within 30 days prior to Screening
18.Any of the following underlying diseases including:
Moderate to severe diabetic retinopathy or any retinopathy with cystoid macular edema.
History or evidence of severe cardiac disease, history or clinical evidence of unstable angina, acute coronarysyndrome, myocardial infarction or revascularization within last six months, ventricular tachyarrythmias requiring ongoing treatment.
History or evidence of clinically significant peripheral vascular disease, such as intermittent claudication or prior amputation.
19. Stroke (within 12 months of trial entry).
20.Any major surgical procedure within one month of trial entry.
21.Positive for Hep B, Hep C or HIV.
22.Treatment with any CYP 3A4 inhibitors/inducers within the last four weeks prior to screening

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To evaluate the safety, tolerability and pharmacokinetic profile of orally administered CTO for 12 weeks for the treatment of neovascular (wet) AMD. This will be done via the collection of adverse event data, blood sample collection to measure drug levels and determine the pharmacokinetic (PK) profile, blood sample collection to ensure parameters remain within the normal range ('normal' for the subject in question), physical exmainations, patient questionnaire completion, echocardiogram (ECG) and general ophthalomologic assessments.[12 weeks];To evaluate the efficacy of orally administered CTO in preventing vision loss in the study eye, as measured by the proportion of subjects who lose fewer than five letters (one line) on best-corrected visual acuity (BCVA) at 12 weeks compared to baseline[12 weeks]