| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| type 2 diabetic patients with stable peripheral or carotid artery disease |
| diabete mellito di tipo 2 e vasculopatia arteriosa periferica o carotidea stabile |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067825 |
| E.1.2 | Term | Peripheral arterial disease |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053247 |
| E.1.2 | Term | Insulin-requiring type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 aim of the present study is to compare the degree of in vivo platelet activation, as reflected by the urinary excretion of the major enzymatic metabolite of thromboxane (TX) A2, 11-dehydro-TXB2 (TXM), in patients with T2DM and stable peripheral or carotid artery disease, randomized to one of two sequences of a cross-over treatment with low-dose aspirin (100 mg od) alone (standard of care) and the combination of low-dose aspirin and low-dose rivaroxaban (2.5 mg bid). |
| Confrontare il livello di attivazione piastrinica in vivo, valutato attraverso l’escrezione urinaria di 11-deidro-trombossano (TX)B2, il principale metabolita enzimatico del TXA2, in pazienti affetti da diabete mellito di tipo 2 e vasculopatia arteriosa periferica o carotidea stabile, randomizzati a aspirina a basse dosi (100 mg una volta al giorno) da sola o in associazione a rivaroxaban a basse dosi (2.5 mg due volte al giorno). |
|
| E.2.2 | Secondary objectives of the trial |
The present study will also compare the effects of the combined treatment vs aspirin alone on the following pharmacodynamic and pharmacokinetic biomarkers:
1. the endothelial anti-thrombotic activity in vivo as assessed by: i) the production of the vasodilator and platelet inhibitor prostanoid, prostacyclin (PGI2) ii) NO biosynthesis as reflected by metabolites involved in its synthesis ; iii) circulating levels of vWF antigen and activity;
2. the oxidative status in vivo, as assessed by the measurement of the urinary excretion of the F2-isoprostane, 8-iso-PGF2a, a product of non-enzymatic lipid peroxidation of arachidonic acid;
3. the inflammatory status, as reflected by the plasma level of cytokines and other inflammation-related biomarkers;
4. anti-FXa activity, as a measure of rivaroxaban Cmax, and thrombin generation potential;
5. platelet cyclooxygenase (COX)-1 activity |
Confrontare il trattamento con basse dosi di aspirina da sola o in associazione a basse dosi di rivaroxaban su biomarcatori di:
1) Attività endoteliale antitrombotica in vivo studiata mediante l’escrezione urinaria di 2,3-dinor-6-keto-PGF1a (PGIM),
2) Stato ossidativo lipidico in vivo, valutato attraverso l’escrezione urinaria di un metabolita non enzimatico dell’acido arachidonico, l’isoprostano 8-iso-PGF2a;
3) Stato infiammatorio ex vivo, valutato attraverso i livelli di citochine infiammatorie circolanti;
4) Attività anti-Fattore Xa, generazione di trombina, test di coagulazione plasmatica standard, livelli di D-dimero;
5) Farmacodinamica dell’aspirina |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria
- T2DM under glucose-lowering treatment;
- PAD defined as having one of the following;18
i) previous aorto-femoral bypass surgery, limb bypass surgery, percutaneous transluminal angioplasty revascularization of the iliac, or infrainguinal arteries;
ii) limb or foot amputation for arterial vascular disease;
iii) intermittent claudication and one or more of either an ankle brachial index (ABI) of less than 0.90 or a peripheral artery stenosis (=50%) documented by angiography or duplex ultrasound;
iv) carotid revascularization or asymptomatic carotid artery stenosis of at least 50% diagnosed by duplex ultrasound or angiography.
Patients with coronary artery disease and ABI <0.90 are also eligible. The ABI is calculated as the ratio of the highest limb systolic blood pressure over the highest brachial systolic blood pressure and Doppler measurements are not required.
- low-dose aspirin since at least 3 months; patients switching from clopidogrel to aspirin need to be on aspirin since at least 4 weeks;
- normal kidney and liver function as defined by creatinine clearance =45 ml/min with the Cockroft-Gault formula [Creatinine Clearance = {((l 40–age) x weight)/(72xSerum Creatinine)}x 0.85 (if female))] and AST and ALT<40 IU/L, according to the normal range of our Centralized Laboratory.
- CAD defined as one of the following:
Myocardial infarction within the last 20 years, or
Multi-vessel coronary disease with symptoms or with history of stable or unstable
angina, that is stenosis of =50% in 2 or more coronary arteries, confirmed by invasive coronary angiography, or non-invasive imaging or stress studies (e.g. exercise or
- 20 -
pharmacologic) suggestive of significant ischemia in 2 or more coronary territories; or in 1 coronary territory if at least one other territory has been revascularized.
Multi-vessel percutaneous coronary intervention (PCI), or
Multi-vessel CABG surgery
- Men and women between 50 and 80 years old
- Women will be recruited only if in a post-menopausal state defined as absence of menses for 12 consecutive months without an alternative medical cause
- Subjects able to understand and sign the informed consent form |
Criteri di inclusione:
- diabete mellito di tipo 2 in trattamento con farmaci ipoglicemizzanti ad eccezione dell’insulina;
- vasculopatia arteriosa periferica, definita come:
¿ Pregresso intervento chiurgico di bypass aorto-femorale, femoro-popliteo, o rivascolarizzazione delle arterie iliache o infra-inguinali, mediante angioplastica percutanea transluminale;
¿ Pregressa amputazione di arto o piede per arteriopatia periferica;
¿ Claudicatio intermittens associata ad almeno uno dei seguenti criteri: Ankle-Brachial Index (ABI) <0.9 o stenosi delle arterie periferiche = 50% documentata mediante angiografia o ecocolorDoppler;
¿ Rivascolarizzazione carotidea o stenosi carotidea asintomatica = 50% documentata mediante angiografia o ecocolorDoppler;
- 4 -
- coronaropatia stabile definita come uno dei seguenti:-
¿ storia di infarto del miocardio negli ultimi 20 anni
¿ coronaropatia multivascolare sintomatica o storia di angina stabile o instabile ovvero come stenosi di almeno il 50% in almeno 2 arterie coronariche mediante angiografia coronarica o imaging non-invasivo o test di stress (e.g. da sforzo o farmacologico) suggestive di ischemia significativa in almeno 2 territori coronarici o in 1 territorio coronarico se almeno 1 altro territorio coronarico è stato già rivascolarizzato
¿ angioplastica coronarica (PCI) o bypass chirurgico (CABG) multi-vascolare
- terapia con aspirina a basse dosi da almeno 3 mesi
- funzionalità epatica nella norma (AST e ALT <40 UI/L) e funzionalità renale conservata (Creatinina Clearance =45 ml/min)
- uomini e donne di età compresa fra i 50 e 80
- le donne saranno arruolate solo se in post-menopausa definita come assenza di ciclo mestruale per almeno i 12 mesi precedenti, consecutivi, in assenza di cause mediche alternative
- soggetti capaci di comprendere e firmare il consenso informato |
|
| E.4 | Principal exclusion criteria |
- Type 1 diabetes mellitus
- Insulin therapy
- Concomitant treatment with antiplatelet drugs other than aspirin
- Ongoing cilostazol treatment
- Co-administration of strong CYP3A4 and P-gp inducers or inhibitors: voriconazole, ketoconazole, itraconazole, posaconazole, anti-HIV drugs such as ritonavir
- Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.)
- Concomitant treatment with any selective serotonin reuptake inhibitor (SSRI) or Serotonin And Noradrenaline Reuptake Inhibitor (SNRI), immunomodulators (ciclosporine, tacrolimus), anti-gout (probenecid); disease-modifier drugs for rheumatoid arthritis (i.e. methotrexate)
- Chronic use of steroids (prednisone >5 mg/die or equivalent)
- Chronic need for nonsteroidal anti-inflammatory drugs (NSAIDs), defined as >3 days/week
- Stroke within 1 month
- Any history of hemorrhagic or lacunar stroke
- Prosthetic heart valves
- Active cancer or cancer in complete remission from less than one year, except for treated early-stage squamous or basal cell skin carcinomas;
- Chronic liver disease
- Congenital or acquired bleeding disorders
- Uncontrolled severe (Stage 4) arterial hypertension
- Gastrointestinal complications (e.g., inflammatory bowel disease, esophagitis, gastritis and gastroesophageal reflux disease) and other disorders without active ulceration that can potentially lead to bleeding
- Recent major surgery (<1 month)
- Women with childbearing potential |
- diabete mellito di tipo 1;
- necessità di terapia insulinica;
- trattamento con farmaci antiaggreganti diversi dall’aspirina,
- terapia in corso con cilostazolo;
- concomitante terapia con farmaci induttori o inibitori forti di CYP3A4 e P-gp: voriconazolo, chetoconazolo, itraconazolo, posaconazolo, farmaci anti-HIV (es. ritonavir);
- fabbisogno cronico di farmaci anti-infiammatori non steroidei (> 3 gg/sett)
- trattamento concomitante con altri anticoagulanti, come le eparine non frazionate, le eparine a basso peso molecolare (enoxaparina, dalteparina, ecc.), i derivati dell’eparina (fondaparinux, ecc.), gli anticoagulanti orali (warfarin, dabigatran etexilato, apixaban, ecc.), - trattamento concomitante con SSRI e SNRI, farmaci antirigetto (ciclosporina, tacrolimus), farmaci antigottosi (probenecid), farmaci per l’artride reumatoide (metotrexate)
- uso cronico di steroidi, es. prednisone >5 mg/die o equivalenti
- ictus recente (< 1 mese)
- qualsiasi pregresso ictus emorragico o lacunare
- protesi valvolari cardiache
- neoplasie in atto o in remissione completa da < 1 anno, ad eccezione del carcinoma basocellulare o squamoso in ‘early stage’ trattati
- epatopatia cronica;
- disordini emorragici congeniti o acquisiti;
- ipertensione arteriosa severa non controllata;
- complicanze gastrointestinali (es. malatte infiammatorie croniche intestinali, esofagite, gastrite o malattia da reflusso gastroesofageo) e altre potenziali condizioni non associate a ulcera gastrica che espongano il paziente ad un potenziale rischio di sanguinamento;
- Intervento recente di chirurgia maggiore (< 1 mese)
- donne in età fertile |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The choice of the primary end-point of the study is based on its primary mechanistic hypothesis. We hypothesize that reduced thrombin formation, resulting from FXa inhibition, will down-regulate persistently enhanced (aspirin-resistant) platelet activation that has been previously characterized in T2DM patients with macrovascular complications (including PAD)(19). Therefore, in comparing the effects of very low-dose rivaroxaban combined with low-dose aspirin vs low-dose aspirin alone, we shall test the hypothesis that combined treatment significantly reduces the urinary excretion of TXM, a non-invasive biomarker of in vivo platelet activation (20), in T2DM patients with stable PAD. The primary comparison will be made between urinary TXM excretion rates measured at the end of each treatment period, with each patient serving as his/her own control. |
| Livelli di 11-deidro-TXB2 misurato al termine di ciascun periodo di 4 settimane di trattamento (vedi Flow Chart). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visit 1: Screening (week - 2).
Visit 2: Randomization (week 0): blood and urine sampling, randomization, initiation of treatment study medication, daily diary assignement (Appendix 10).
Visit 3 (week 2): blood and urine sampling, study medication accountability (pill count), daily diary collection and new diary assignement.
Visit 4: (week 4): blood and urine sampling, study medication accountability (pill count), daily diary collection and new diary assignement. Crossover treatment.
Visit 5 (week 6): blood and urine sampling, study medication accountability (pill count), daily diary collection and new diary assignement.
Visit 6: (week 8): end of treatment; blood and urine sampling, study medication accountability (pill count), diary collection. |
Visita 1: screening
Visita 2: randomizzazione e inizio trattamento
Visita 3: valutazione a 2 settimane
Visita 4: valutazione a 4 settimane
Visita 5: valutazione a 6 settimane
Visita 6: valutazione a 8 settimane e fine trattamento |
|
| E.5.2 | Secondary end point(s) |
. In vivo endothelial function:
- endothelial anti-thrombotic activity will be assessed by measuring in vivo PGI2 biosynthesis, as reflected by the urinary excretion of its major enzymatic metabolite, 2,3-dinor-6-keto-PGF1¿ (PGIM);
- the NO biosynthetic pathway as reflected by the analytes involved in its synthesis, i.e Arginine, the substrate of NO synthase and its products, Citrulline and Ornitine and the synthesis inhibitors, MMA, SDMA and ADMA;
- vWF antigen and activity levels;
2. The following pro- and anti-inflammatory cytokines will be measured in peripheral venous blood: IL-2, IL-6, IL-9, IL-10, TNF-alpha.
3. Rivaroxaban plasma peak level (2 to 4 hr after dosing), as reflected by the anti-Xa activity, will be measured.
4. The urinary isoprostane, 8-iso-PGF2¿ will be measured as an index of in vivo lipid peroxidation, as previously described (16).
5. Serum TXB2 will be measured as a biomarker of aspirin pharmacodynamics, to assess the adequacy of platelet COX-1 inhibition, as previously described (16).
6. D-dimer level during the run-in period and on the last day of each period of the randomized treatment schedule (see below). |
1) Livelli di escrezione urinaria di PGIM, metaboliti plasmatici dell’ossido nitrico e fattore di von Willebrand
2) Livelli di escrezione urinaria di isoprostano urinario 8-iso-PGF2a.
3) Concentrazione plasmatica di Interleukine -2, -6, -9, -10, TNFa
4) Concentrazione plasmatica massima di rivaroxaban (Cmax) misurata come attività anti-FXa tra 2 e 4 ore dopo la somministrazione ambulatoriale del mattino
5) Livelli di TXB2 sierico
6) Livelli di D-dimero |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As in Primary endpoints |
| Come in end point primario |
|
| 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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Pathogenetic mechanisms of drug response |
| Meccanismi patogenetici di risposta alla terapia |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | Information not present in EudraCT |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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