E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetes type 2: neuropathic symptoms |
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E.1.1.1 | Medical condition in easily understood language |
Patients with type 2 diabetes often experience symptoms of nerve disease in the extremities. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
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 |
The primary purpose of this double blind study is to determine the effect of ARA 290 on neuropathic symptoms in patients with type 2 diabetes.
Amendment(Jul2014): 1) to determine insulin oscillations, 2) to determine whether ARA 290 administration increases insulin secreted to a glucose stimulus in a dose dependent manner as in the GK rat model and 3) whether extending the period of daily administration of ARA 290 to three months improves further glucose and lipid control and neuropathic symptoms in diabetic patients with small fiber neuropathy and whether these improvements are accompanied by improved systemic insulin oscillations |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess the effects of ARA 290 on general health and well-being, quantitative sensory testing, intra epidermal nerve fiber densities, cardiac autonomic neuropathy (as determined by R-R AND QT interval variability/changes in the ECG), 6 minute walk test, and visual acuity as determined by ETDRS chart evaluation in these patient populations. Additionally, the effect of ARA 290 on glucose control and microalbuminuria will be assessed. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Established diagnosis of diabetes mellitus type 2
Screening HbA1c between 7.5 % and 10 % inclusive [retest of HbA1c allowed for patients with borderline values]
Quantitative sensory testing shows allodynia and altered temperature thresholds
Spontaneous discomfort level of 6 or greater on Pain Now (Pain Detect; 0 (least discomfort)-10 (worst discomfort))
and small fiber neuropathy screening list (SFNSL; [1]) > 22,
or spontaneous discomfort level on Pain Now (Pain Detect) < 5 and SFNSL > 44 at screening AND at first dosing visit.
Discomfort defined as distal pain/discomfort plus one of the following: 1) paresthesia 2) burning/painful feet worsening at night, or 3) intolerance of sheets or clothes touching the legs or feet
Be able to read and understand the written consent form, complete study-related procedures, and communicate with the study staff
Be willing to comply with study restrictions
Be willing to check in with the study center via the telephone
Between 18 and 70 years of age (inclusive)
Body Mass Index (BMI) < 40 kg/m2 (inclusive)
If female of childbearing potential, a negative urine pregnancy test at screening and acceptable contraception will be maintained during the screening and dosing period and 1 month beyond. Acceptable contraception consists of hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the patient’s usual menstrual cycle period) before study entry, intrauterine device (IUD), or double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream).
Able to complete self-administered questionnaires (RAND-36, SFNSL, Pain Detect)
Refrigerator at home for storage of study medication.
Amendments (May2014): HbA1c >8% at screening, able to visit the hospital sober |
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E.4 | Principal exclusion criteria |
Clinically relevant abnormal history of physical and mental health other than conditions related to diabetes, as determined by medical history taking (as judged by the investigator)
Clinically relevant abnormal laboratory results, vital signs, or physical findings other than conditions related to diabetes (as judged by the investigator)
Known clinically relevant abnormalities in ECG (as judged by the investigator)
Episodes of significant hypoglycemia (as judged by the investigator)
Illicit drug abuse or excessive alcohol consumption (as judged by the investigator)
History of serious malignancy (as judged by the investigator)
History of severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food (as judged by the investigator)
Subjects that received a vaccination or immunization within the month prior to screening.
Anti-TNF therapy or other biological anti-inflammatory agents administered within the 6 months prior to screening.
Use of erythropoiesis stimulating agents within the two months prior to screening or during the trial
Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug or more than 4 times per year
Inadequate venous accessibility as judged by clinicians (physician or nurse)
Inability or unwillingness to self-administer ARA 290 via subcutaneous injections (or not have access to home health care for assistance in administration; also see 6.9)
If female, pregnant or breast-feeding
Any other condition that in the opinion of the investigator would complicate or compromise the study, or the well being of the patient |
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E.5 End points |
E.5.1 | Primary end point(s) |
Collection of adverse events, serious adverse events, and laboratory parameters
Change in hemoglobin A1c at day 28 and 56 compared to baseline
Change in the scores of the Small Fiber Neuropathy Screening List, Pain Detect, and RAND-36 (pain and physical function components) at days 28, 56, and 84 compared to screening
Amendment (Jul2014): Insulin oscillations, Intravenous Glucose Tolerance Test over 2 hours with frequently-sampled plasma glucose and insulin concentrations with ARA 290 4 mg administered during the course of the GTT . |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Pre-treatment, day 28, day 56 and day 84
Insulin oscillations: sample every 2 minutes for one hour |
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E.5.2 | Secondary end point(s) |
Change in quantitative sensory testing at day 28 baseline
Change in intra epidermal nerve fiber density at day 28 baseline
Change in the 6 minute walk test at day 28 versus baseline
Change in visual acuity at day 28 versus baseline
Change in heart rate variability (R-R and QT intervals) at day 28 versus baseline
Change in visual acuity at 28 and 56 days versus baseline
Additionally, the effect of ARA 290 on glucose control, C reactive protein, and microalbuminuria in patients with diabetes will be assessed.change in fasting glucose at day 28 versus screening
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pre-treatment, day 28, day 56 |
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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 | Yes |
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) | 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 | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 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 | 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
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |