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Trial registered on ANZCTR


Registration number
ACTRN12612001130853
Ethics application status
Not yet submitted
Date submitted
15/10/2012
Date registered
23/10/2012
Date last updated
23/10/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
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)
Scientific title
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)
Secondary ID [1] 281377 0
n/a
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neovascular Age Related Macular Degeneration 287605 0
Condition category
Condition code
Eye 287938 287938 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
CTO (Carboxyamidotriazole Orotate) is an oral (capsule) preparation to be admninstered once daily with an overall trreatment duration of 12 weeks. Doses to be administered will follow a cohort process into which eligible subjects will be enrolled sequentially. Cohort 1 (4mg/Kg), Cohort 2 (8mg/Kg) & Cohort 3 (12mg/Kg). Since only one eye is selected for examining the effects of the drug (if any) ie. for meeting the ojectives of the study, the other eye is nominated as the 'non-study' eye. The non-study eye will still undergo the same ophthalomogical assessments as the study eye. The only time this non-study eye will be assessed for 'outcomes' is if Choroidal Neovascularisation is detected (CNV).
Intervention code [1] 285874 0
Treatment: Drugs
Comparator / control treatment
There is no control group for this trial. However, dosing will be escalated up to (or reduced down to) a Maximum Tolerated Dose (MTD). This will then be expanded to enrol more subjects to determine further, the safety profile of the drug. A total of 27 subjects will be enrolled into this trial. The number of subjects allocated to the expansion phase of the trial will be determined by the number of subjects enrolled during the escalation phase ie. if 9 subjects were required to justify the escalation to cohort 1, then 18 subjects will be enrolled in the expansion phase ie 27-9=18.
Control group
Active

Outcomes
Primary outcome [1] 288156 0
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.
Timepoint [1] 288156 0
12 weeks
Primary outcome [2] 288159 0
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
Timepoint [2] 288159 0
12 weeks
Secondary outcome [1] 299528 0
To determine the proportion of subjects who gained at least 15 letters on BCVA in the study eye at 12 weeks compared to baseline. This will be achived using the Early Treatment Diabetic Retinopathy Study (EDTRS) logMAR chart assessment.
Timepoint [1] 299528 0
12 weeks
Secondary outcome [2] 299529 0
To determine the proportion of subjects who maintained BCVA (plus or minus five letters) in the study eye at 12 weeks compared to baseline. This will be achieved using the Early Treatment Diabetic Retinopathy Study (EDTRS) logMAR chart assessment where the subject will be required to read a series of letters from a chart that is placed at a set distance from the subject.
Timepoint [2] 299529 0
12 weeks
Secondary outcome [3] 299530 0
To evaluate the efficacy of orally administered CTO on the size of choroidal neovascularisation (CNV) and the amount of leakage from CNV in the study eye at 12 weeks, as assessed by fluorescein angiography.
Timepoint [3] 299530 0
12 weeks
Secondary outcome [4] 299531 0
To evaluate the efficacy of orally administered CTO on the change in mean central retinal subfield thickness measure by optical coherence tomography (OCT) from baseline in the study eye at 12 weeks.
Timepoint [4] 299531 0
12 weeks
Secondary outcome [5] 299532 0
To evaluate the fellow (non-study) eye following orally administered CTO if CNV is present. CNV will be detected by Flourescein Angiography (FA)and Optical Coherence Tomography(OCT). The methods used will be to measure change in lesion size, leakage from CNV, the area of subretinal fuid (SRF) and change in OCT thickness.
Timepoint [5] 299532 0
12 weeks

Eligibility
Key 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.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Subjects will be allocated sequentially to the study, and to one of the three cohorts which (at the time of enrollment) is active.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The Cohorts and subject enrollment will be managed centrally. The permission to enroll a subject will be provided following the receipt of a Subject enrollment Request Form. The subject will then be allocated to the next available slot/cohort, in a sequential manner.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Dose escalation, dose-expansion.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
27
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 4594 0
New Zealand
State/province [1] 4594 0

Funding & Sponsors
Funding source category [1] 286151 0
Self funded/Unfunded
Name [1] 286151 0
Rashida Karmali
Country [1] 286151 0
United States of America
Primary sponsor type
Individual
Name
Rashida Karmali
Address
Tactical Therapeutics, Inc.
99 Wall Street, 23rd Fl
New York, NY 10005
Country
United States of America
Secondary sponsor category [1] 284959 0
Commercial sector/Industry
Name [1] 284959 0
INC Research
Address [1] 284959 0
Level 1, 20 Atherton Road
Oakleigh VIC 3166
Country [1] 284959 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 288210 0
Ethics committee address [1] 288210 0
Ethics committee country [1] 288210 0
Date submitted for ethics approval [1] 288210 0
26/09/2012
Approval date [1] 288210 0
Ethics approval number [1] 288210 0

Summary
Brief summary
The purpose of this trial is to test 3 dose levels of an investigational drug in people with the medically diagnosed eye condition 'Age-related Macular Degeneration' (AMD). You will be allocated to a cohort in a sequential/rolling manner, depending on the time that you are screened for the trial. The aim is to find the optimum dose that is not only safe but may also have a beneficial effect on the condition. During the course of the trial, you will certain assessments conducted such as having blood samples taken, ophthalmologic assessments. physical exams and having certain photographs/images take of the eye. These will enable the objectives of the trial to be assessed.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 34817 0
Address 34817 0
Country 34817 0
Phone 34817 0
Fax 34817 0
Email 34817 0
Contact person for public queries
Name 18064 0
Alex Seta
Address 18064 0
INC Research
Level 1, 20 Atherton Road
Oakleigh VIC 3166
Country 18064 0
Australia
Phone 18064 0
+61 3 8533 6804
Fax 18064 0
+61 3 9567 7699
Email 18064 0
[email protected]
Contact person for scientific queries
Name 8992 0
Rashida Karmali
Address 8992 0
Tactical Therapeutics, Inc.
99 Wall Street, 23rd Fl
New York, NY 10005
Country 8992 0
United States of America
Phone 8992 0
+1 212-651-9653
Fax 8992 0
+1 212-651-9654
Email 8992 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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