E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of diabetic foot ulcer |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of diabetic foot ulcer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012684 |
E.1.2 | Term | Diabetic peripheral vascular disease |
E.1.2 | System Organ Class | 100000004866 |
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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 |
Investigate the changes in resting blood flow speed in skin capillaries before and after study drug administration.
Investigate the change in peak capillary blood flow speed during a temporary increase in blood flow (reactive hyperemia) before and after study drug administration.
Investigate the change in time to peak capillary blood flow speed during a temporary increase in blood flow (reactive hyperemia) before and after study drug administration.
Investigate the change in oxygen pressure through the skin before and after study drug administration |
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E.2.2 | Secondary objectives of the trial |
Analyse the safety and tolerability of BAY 1193397 after a single dose administration as evidenced by the incidence and severity of adverse events |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The informed consent must be signed before any study specific tests or procedures are done (patient must be able to give informed consent, no legal representative allowed)
- Patients with a diagnosis of type II diabetes mellitus and PAD and/or microangiopathy as evidenced by at least one of the following criteria:
a) TBPI < 0.7 at screening
b) ischaemic or neuro-ischaemic DFU in medical history (verified by medical records)
c) clinical diagnosis of PAD in medical history (verified by medical records)
d) diagnosis of nephropathy that is most likely due to diabetes mellitus type II
e) diagnosis of diabetic retinopathy
f) diagnosis of diabetic polyneuropathy
- Age 55 to 75 years (inclusive) at the screening visit
- Non-smokers are preferred for inclusion in this study. If smokers are included, they must refrain from smoking on the days of treatment periods 1, 2, and 3 until all examinations have been performed
- Patients are expected to be on stable medication during study conduct. No planned changes in drug therapy during active treatment period of the study (i.e. from treatment period 1 to treatment period 3) is allowed
- Men or confirmed postmenopausal women (defined as exhibiting spontaneous amenorrhea for at least 12 months before screening or as exhibiting spontaneous amenorrhea for 6 months before screening with documented serum follicle-stimulating hormone [FSH] levels > 40 mIU/mL) or women without childbearing potential based on surgical treatment 6 weeks before screening such as bilateral tubal ligation, bilateral oophorectomy with or without hysterectomy (documented by medical report verification). Male patients, who are sexually active and have not been surgically sterilized must agree to use two reliable and acceptable methods of contraception simultaneously (one method used by the study patient and one method used by the partner) during the study and for 12 weeks after receiving the investigational medicinal product and not to act as sperm donor for 12 weeks after dosing. Acceptable methods of contraception include for example: a) condoms (male or female) with or without a spermicidal agent b) diaphragm or cervical cap with spermicide c) intrauterine device d) hormone-based contraception
- Ability to understand and follow study related instructions
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E.4 | Principal exclusion criteria |
Medical and surgical history
- Patients with existing lower limb ulcers
- Patients with nailfold capillaries at the great toe that are technically difficult to assess
- Patients suffering from PAD Fontaine Stage 4
- Patients requiring planned revascularization
- Patients suffering from diseases other than diabetes mellitus that are known to lead to disturbances in skin microcirculation or interfering with the method of measurement such as Raynaud’s disease, collagen vascular disorders , atopic dermatitis, psoriasis
- Patients with diabetes mellitus induced by immunosuppressive treatment
- Patients with renal replacement therapy
- Patients with organ transplants
- Medical history of autoimmune disease
- Myocardial infarction, acute coronary syndrome, transient ischemic attack (TIA),
stroke, revascularization, angioplasty within 3 months prior to randomization
- Any planned surgical intervention during the course of the study
- Medical condition or history thereof or any deviation from normal laboratory values that in the opinion of the investigator would impair the ability to complete the planned study procedures
- Any surgical or medical condition which significantly alters absorption, distribution, metabolism or excretion of study drugs, including, but not limited to: history of major gastrointestinal (GI) tract surgery, inflammatory bowel disease, currently active gastritis, pancreatitis, treatment with cholestyramine and colestipol resins
- Patients with HbA1c > 12% (> 108 mmol/mol) at the screening visit
- Any other condition or therapy, which would make the subject unsuitable for this study and will not allow participation for the full planned study period (e.g. active malignancy or other condition limiting life expectancy to less than 12 months)
Medication, drug use and special behavioral patterns
- Use of alpha or beta AR agonists
- Use of alpha AR antagonists
- Use of serotonin/norepinephrine reuptake inhibitors (SNRIs)
- Use of tricyclic antidepressants at a dose equivalent of more than 50 mg amitryptyline
- Use of strong CYP 3A4 inhibitors (as specified in the study protocol) within 7 days prior to first administration and until follow-up. Topical use of antifungal cream is allowed.
- Use of strong CYP 3A4 inducers (as specified in the study protocol) within 7 days prior to first administration and until follow up Consumption of grapefruit (juice or fruit) within 7 days prior to first administration and until follow-up
- Use of St John´s wort within 7 days prior to first administration and until follow-up
- Suspicion of drug or alcohol abuse
- Donation of more than 100 / 500 mL of blood within 4 weeks / 3 months prior to screening
- Known hypersensitivity to the study drugs (active substances or excipients of the preparations)
- No pedicure or nail polish is allowed from screening until the end of the active study period (end of treatment period 3)
ECG, blood pressure, heart rate
- Clinically relevant findings in the ECG, such as a second- (type Mobitz II) or thirddegree AV block, or QTc elevation as follows:
- > 450 msec in patients without a complete bundle branch block
- > 480 msec in patients with a complete bundle branch block
- > 500 msec in patients with a right ventricular paced rhythm
- Systolic blood pressure below 100 mmHg or above 180 mmHg at the screening visit based on the average of three readings taken from the arm with the highest systolic recordings
- Diastolic blood pressure below 50 or above 110 mmHg at the screening visit based on the average of three readings taken from the arm with the highest systolic recordings
- Heart rate below 50 or above 100 beats/min at screening (obtained from ECG)
Physical examination
- Clinically relevant findings in the physical examination which, in the opinion of the investigator, preclude participation for reasons of the patient’s safety
Laboratory examination
- Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) formula at screening
- Anemia as evidenced by hemoglobin values < 10 mg/dL at screening
- Hepatic impairment as evidenced by aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or gamma-glutamyl transpeptidase (GGT) threefold above upper limit of normal (ULN) and, in addition, bilirubin twofold above ULN
Other
- Previous assignment to treatment during the study
- Previous (within 30 days or 5 half-lives prior to screening, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s)
- Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site)
- Patient is in custody by order of an authority or court of law
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in resting CBV (capillary blood flow velocity) (= resting CBV after study drug administration – resting CBV before study drug administration)
- Change in peak CBV during reactive hyperemia (= peak CBV after study drug administration – peak CBV before study drug administration)
- Change in time to peak CBV during reactive hyperemia (= time to peak CBV after study drug administration – time to peak CBV before study drug administration)
- Change in foot TcPO2 (transcutaneous oxygen pressure) (= TcPO2 after study drug administration – TcPO2 before study drug administration)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 hour after administration of study drug at visits 2,3,4 |
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E.5.2 | Secondary end point(s) |
Incidence and severity of adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After administration of study drug at visits 2,3,4 |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
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 | 3 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 17 |