| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory breathlessness in patients diagnosed with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD). |
| La dispnea refrattaria/cronica in pazienti affetti da broncopneumopatia cronica ostruttiva (BPCO) e malattia polmonare interstiziale (ILD). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breathlessness that continues despite optimal management of the underlying causes and current symptom relief measures, in patients suffering from lung disease. |
| Dispnea persistente nonostante trattamento ottimale delle cause e dei sintomi in pazienti affetti da patologie polmonari |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| 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 | 10009032 |
| E.1.2 | Term | Chronic obstructive lung disease |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 |
| To determine whether mirtazapine is an effective treatment for the reduction of self-reported worst breathlessness over the past 24 hours measured at day 56 post start of treatment compared to placebo in patients with COPD (Chronic Obstructive Pulmonary Disease) or ILD (Interstitial Lung Disease) in palliative and end of life care. |
| Determinare se la Mirtazapina è un trattamento efficace per la riduzione della peggiore dispnea auto-riportata (misurata attraverso la scala numerica NRS a 56 giorni dall’inizio del trattamento con Mirtazapina o placebo) in pazienti con dispnea cronica o refrattaria confrontandola con la peggiore dispnea riportata alla visita basale |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the effectiveness of mirtazapine, compared to placebo, over time at days 7,14, 28, 56 & 180
- To evaluate safety, toxicity and tolerability of mirtazapine
- To identify which patient characteristics are most associated with benefit from mirtazapine, specifically assessing the impact of age: gender; functional status; aetiology; and baseline intensity of: breathlessness and its characteristics; anxiety; depression; and concomitant opioid administration
- To assess the cost-effectiveness of mirtazapine treatment from a societal perspective (i.e. including formal and informal care received), when compared with best standard care
- To demonstrate the feasibility of delivering mirtazapine treatment across the different European countries in terms of acceptability of the offered treatment and compliance with treatment
- To evaluate the impact of patients receiving mirtazapine on caregivers, in particular primary caregiver reports of their time in hours, burdens and experiences |
- valutare l'efficacia della mirtazapina, rispetto al placebo, ai giorni 7,14, 28, 56 e 180
- valutare sicurezza, tossicità e tollerabilità della mirtazapina
- Identificare le caratteristiche principali del paziente associate al beneficio della mirtazapina, in particolare l'impatto dell'età: sesso; stato funzionale; eziologia; e intensità di base di: dispnea e sue caratteristiche; ansia; depressione; e somministrazione concomitante di oppioidi
- Valutare il rapporto costo-efficacia del trattamento con mirtazapina in una prospettiva sociale ( compresa l'assistenza formale e informale ricevuta), rispetto alle migliori cure standard
- Dimostrare la fattibilità del trattamento nei diversi paesi europei in termini di accettabilità del trattamento offerto rispetto al trattamento standard
- |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Life quality
Version: 7.0
Date: 23/10/2020
Title: The BETTER-B sub-study is the Caregiver sub-study.
Objectives: The aim of this sub study is to assess the caregiver burden and the experience of the participants caregivers and close family members.
|
Qualita' della vita
Versione: 7.0
Data: 23/10/2020
Titolo: BETTER-B - qualità della vita del Caregiver.
Obiettivi: Lo scopo di questo studio secondario è valutare il carico del caregiver e l'esperienza dei partecipanti che si prendono cura di loro e dei familiari stretti.
|
|
| E.3 | Principal inclusion criteria |
1.Aged = 18 years old
2.Diagnosed with:
•Chronic obstructive pulmonary disease (COPD), or
•Interstitial lung disease (ILD) including chronic fibrotic lung disease following SARS-CoV-2 infection
3.Breathlessness severity: Modified MRC breathlessness scale of:
•grade 3 (I stop for breath after walking about 100 yards or after a few minutes on level ground) or
•Grade 4 (I am too breathless to leave the house or I am breathless when dressing or undressing)
4.On optimal treatment of the underlying condition in the opinion of the identifying clinician
5.Management of the underlying condition unchanged for the previous 2 weeks
6.Reversible causes of breathlessness optimally treated in the opinion of the identifying clinician
7.If female, must be (as documented in patient notes):
a)postmenopausal (no menses for 12 months without an alternative medical cause), or
b)surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or
c)using acceptable contraception (which must be continued for 7 days after the last dose of IMP)
8.Able to complete questionnaires and trial assessments
9.Able to provide written informed consent
Caregiver eligibility:
Caregivers will be identified by an included patient participant as the
person closest to them, providing the patient participant is willing for
them to be approached.
Caregivers must meet all of the following criteria to be eligible:
1.Identified by an included patient as the person closest to them
2.Aged =18 years old
3.Able to complete questionnaires and assessments
4.Able to provide written informed consent |
1. Età > 18 anni
2. Diagnosi di:
• Malattia polmonare cronica ostruttiva (BPCO) e / o
• Malattia polmonare interstiziale (ILD), inclusa la malattia polmonare fibrotica cronica post SARS-CoV-2
3. Severità della dispnea valutata secondo scala MRC modificata (nMRC)
• Grado 3 (Mi fermo per respirare dopo aver camminato per circa 90 metri dopo alcuni minuti su una superficie
piana
o
• Grado 4 (Sono senza fiato per uscire di casa e, mi manca il fiato quando mi vesto e mi spoglio)
4. Giudizio clinico idoneo al trattamento (consultare sezione Errore. L'origine riferimento non è stata trovata. del protocollo)
5. Condizione clinica invariata nelle ultime 2 settimane
6. Cause reversibili di affanno sono state trattate nel miglior modo, secondo l'opinione del clinico che ha in cario il paziente
7. Se il pazinete è di sesso femminile , deve essere (come documentato nel
foglio informativo per il paziente):
a) in fase post menopausa (intesa come assenza del ciclo mestuale da almeno 12 mesi) o
8. b) sterilità chirurgica (isterectomia, salpingectomia bilaterale o ooforectomia bilaterale), o
c) uso di contraccetivi (che deve essere continuato fino a 7 giorni dopo l’ultima dose di IMP assunta)
8. abile a completare i questionari e le visite di studio
9. in grado di fornire consenso informato scritto |
|
| E.4 | Principal exclusion criteria |
1.Existing antidepressant use, or other serotonergic active substances
(e.g. linezolid, St John's wort)
2.Known contraindication to mirtazapine
3.Hypersensitivity to the active substance or to any of the components of
mirtazapine or placebo (e.g. lactose intolerance)
4.Australia modified Karnofsky Performance Scale =40
5.Pregnant or breast-feeding women. For women of childbearing
potential (those not post-menopausal or surgically sterile) this must be
confirmed by a pregnancy test (urine) within 7 days prior to
randomisation
6.Patients with known cardiovascular disease or acute cardiac events
within 3 months prior to randomisation (e.g. myocardial infarction,
unstable angina pectoris, or significant cardiac conduction disturbance)
7.Patients with jaundice or known hepatic impairment in the opinion of
the identifying clinician (e.g. bilirubin >25micromol/L, and AST and ALT
>2 times upper limit of normal)
8.Patients with known renal impairment in the opinion of the identifying
clinician (e.g. creatinine >132micromol/L and eGFR
<30mL/min/1.73m2)
9.Patients with uncontrolled blood pressure in the opinion of the
identifying clinician
10.Patients with uncontrolled diabetes mellitus in the opinion of the
identifying clinician
11.Patients with uncontrolled seizures, epilepsy or organic brain
syndrome in the opinion of the identifying clinician
12.Patients with severe depression or suicidal thoughts in the opinion of
the identifying clinician
13.Patients with a history of psychotic illness (schizophrenia, or other
psychotic disturbances) in the opinion of the identifying clinician
14.Patients with bipolar disorder, or a history of mania or hypomania in
the opinion of the identifying clinician
15.Patients currently enrolled in another interventional trial
16.Patients with known congenital QT prolongation or family history for
QT prolongation
17.Use of medicines that cause QT prolongation such as macrolides and
typical antipsychotics (unless required in low-dose to relieve nausea,
e.g. haloperidol =5mg/24h, levomepromazine =25mg/24h)
18.Patients with a known history of suicide-related events |
1. Uso di antidepressivi o altri principi attivi serotoninergici (ad es. Linezolid,
iperico)
2. Nota controindicazione all’utilizzo di Mirtazapina
3. Ipersensibilità al principio attivo o ad uno qualsiasi dei componenti di Mirtazapina o placebo (ad es. Intolleranza al lattosio)
4. Australia modified Karnofsky Performance Scale =40
5. Donne in gravidanza o in allattamento. Per le donne in età fertile (non post-menopausa o chirurgicamente sterili) lo stato di NON gravidanza deve essere confermato da un test di gravidanza (urine) eseguito non
oltre I 7 giorni dalla randomizzazione
6. Pazienti che hanno avuto eventi cardiaci acuti entro 3 mesi prima dalla randomizzazione (infarto del miocardio, angina pectoris instabile o disturbo significativo della conduzione cardiaca) possono essere arruolati
a secondo del giudizio del clinico che ha in carico il pz
7. Pazienti con ittero o compromissione epatica possono essere arruolati a seconda del giudizio del clinic che ha in carico il paziente
8. Pazienti con insufficienza renale nota possono essere arruolati a seconda del giudizio del clinic che ha in carico il paziente
9. Pazienti con ipertensione incontrollata possono essere arruolati a seconda del giudizio del clinic che ha in carico il paziente
10.Pazienti con diabete mellito incontrollato possono essere arruolati a seconda del giudizio del clinic che ha in carico il paziente
11.Pazienti con convulsioni incontrollate, epilessia o sindrome cerebrale possono essere arruolati a seconda del giudizio del clinic che ha in carico il paziente
12.Pazienti con grave depressione o pensieri suicidi possono essere arruolati a seconda del giudizio del clinic che ha in carico il paziente
13.Pazienti con storia di malattia psichiatrica (schizzofrenia, o altri disturbi psichiatrici) possono essere arruolati a seconda del giudizio del clinico che ha in carico il paziente
14.Pazienti con disturbi bipolari, o con storia di mania o ipomania possono essere arruolati a giudizio del clinic che ha in carico il paziente
15.Pazienti attualmente arruolati in altri studi interventistici
16.Pazienti con prolungamento dell’intervallo QT congenito o con familiarità di prolungamento dell’intervallo QT
17. Uso di medicinali che causano prolungamento dell'intervallo QT come macrolidi e antipsicotici tipici (a meno che non sia richiesto a basse dosi per alleviare la nausea, ad es. Aloperidolo =5 mg / 24 ore,
levomepromazina =25 mg / 24 ore)
18. Pazienti con precedenti eventi associati a tentativi di suicidio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to determine whether mirtazapine is an effective treatment for the reduction of self-reported worst breathlessness over the past 24 hours measured at day 56 post start of treatment compared to placebo in patients with COPD or ILD in palliative and end of life care. The primary endpoint is worst breathlessness over the last 24 hours at day 56 post start of treatment as assessed by numerical rating scale (NRS, 0=no breathlessness to 10=worst possible breathlessness). Day 56 post start of treatment was chosen to allow sufficient time for the intervention to have an effect, it is a timescale which will be useful in palliative and end of life care and we can collect the primary outcome without too much attrition. |
| L'obiettivo primario è determinare se la mirtazapina è un trattamento efficace per la riduzione della peggiore dispnea auto-segnalata nelle ultime 24 ore misurata al giorno 56 dopo l'inizio del trattamento rispetto al placebo nei pazienti con BPCO o ILD in cure palliative e di fine vita . L'endpoint primario è la peggiore dispnea nelle ultime 24 ore al giorno 56 dopo l'inizio del trattamento, come valutato dalla scala di valutazione numerica (NRS, da 0 = assenza di respiro a 10 = peggior dispnea possibile). Il giorno 56 dopo l'inizio del trattamento è stato scelto per consentire un tempo sufficiente affinché l'intervento abbia un effetto, è un lasso di tempo che sarà utile nelle cure palliative e di fine vita e possiamo raccogliere l'esito primario senza troppi attriti. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary outcome will be evaluated when participants have reached day 56 post start of treatment. |
| L'outcome primario sarà valutato al giorno 56 dopo l'inizio del trattamento. |
|
| E.5.2 | Secondary end point(s) |
•Worst & average breathlessness over the last 24 hours as assessed by NRS at days 7, 14, 28 and 180 post start of treatment
•Number & duration of episodes of breathlessness over the last 24 hours
•Physical & emotional aspects of breathlessness as assessed by the Chronic Respiratory Questionnaire (CRQ) at days 14, 28, 56 and 180 post start of treatment
•Physical symptoms as assessed by the IPOS at days 14, 28, 56 and 180 post start of treatment
•QoL as assessed by the EQ-5D-5L and associated VAS at days 14, 28, 56, 180 post start of treatment and AKPS at days 14, 28, 56 and 180
•Anxiety & depression as assessed by the Hospital Anxiety and Depression Scale (HADS) at days 28, 56 and 180
•Perceived self-efficacy as measured by the Generalized Self-Efficacy Scale (GSES) at day 56 post start of treatment
• Opioid medication usage at days 7, 14, 28, 56 and 180
•Healthcare services received within 28 and 56 days post start of treatment and in the 3 month period prior to day 180 post start of treatment as measured by the Client Services Receipt Inventory
(CSRI)
•Safety as assessed by the occurrence of:
oSAEs, SARs and SUSARs at days 7, 14, 28 and 56 post start of treatment
oDeaths by day 56 and day 180 post start of treatment
•Toxicity as assessed by adverse reactions (ARs) coded according to mild, moderate or severe as reported at days 7, 14, 28 and 56 post start of treatment
•Tolerability as assessed by the proportion of patients not withdrawing due to adverse reactions
•Baseline demographics & characteristics will be measured to enable prognostic evaluation of those factors most associated with benefit from mirtazapine (benefit as measured by worst breathlessness over the last 24 hours at day 56 post start of treatment. Specifically assessing:
oage
ogender
ofunctional status, aetiology
obaseline intensity of breathlessness
oanxiety and depression (as measured by HADS)
oconcomitant opioid administration
•Formal and informal care use over the previous period as measured by the CSRI at days 28, 56 and 180 post start of treatment, to examine hours of care and (using country specific unit costs) costs of services
•Acceptability of the offered treatment as assessed by the recruitment conversion rate, the number of people withdrawing from treatment, and the number of participants who request mirtazapine from their
doctor/clinician after 56 days post start of treatment
•Treatment compliance as measured by the:
oproportion and type of dropouts over 56 days post start of treatment,
oproportion of tablets taken over 56 days post start of treatment,
oproportion of participants who escalate dose at days 14 and 28 post
start of treatment
oOff trial treatment compliance to 180 days post start of treatment
•Caregiver's perceived impact on the participant and themselves as measured by:
oWorst & average rating of the participant's breathlessness over the last 24 hours as assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 28, 56 and 180 post start of treatment
oCaregiver assessment of the participant's number and duration of episodes of breathlessness over the last 24 hours
oInformal care hours as measured by the CSRI at days 28, 56 and 180 post start of treatment
oCaregiver self-reported burden as measured by the Zarit Burden interview at days 28, 56 and 180 post start of treatment
oCaregiver self-reported experiences of caregiving as measured by the Positive Aspects of Caregiving scale at days 28, 56 and 180 post start of treatment;
oCaregiver perspectives on participants' situation as measured by the
Integrated Palliative care outcome scale at days 28, 56 and 180 post start of treatment
oCaregiver overall health and wellbeing as measured by EQ-5D-5L and associated VAS at days 28, 56 and 180 post start of treatment
oCaregiver perspectives on how participants would rate their own overall health & wellbeing as measured by the proxy EQ-5D-5L & associated VAS at days 28, 56 and 180 post start of treatment |
Valutare l’efficacia della Mirtazapina rispetto al placebo ai giorni 7,14,28,56 e 180 dall’inizio del trattamento, valutando:
o La peggiore dispnea e la dispnea media nelle ultime 24h Misurata con la scala NRS riportata dal paziente:
o Altri sintomi fisici (misurati dal questionario CRQ e IPOS completato dal paziente) e della qualità della vita complessiva (misurati da AKPS e EQ-5D-5L completati dal paziente completato dal paziente e dal caregiver (solo al giorno 28, 56 180);
o Ansia, depressione (misurata da HADS) e senso di autoefficacia percepita (misurata da GSES)
o Il consumo di oppioidi
o Accessi in ospedale, in particolare accessi non programmati (accessi in PS con co senza ricovero) rilevati dal questionario CSRI.
• Valutazione della safety, della tossicità e della tollerabilità della Mirtazapina.
• Identificare quali caratteristiche del paziente sono maggiormente associate ai benefici della Mirtazapina, valutando specificamente l'impatto dell'età: sesso; stato funzionale; eziologia; e intensità di base di: mancanza di respiro e le sue caratteristiche; ansia; depressione; e concomitante somministrazione di oppioidi.
• Valutare il rapporto costo-efficacia del trattamento con Mirtazapina dal punto di vista sociale (ovvero includendo le cure formali e informali ricevute), rispetto alle migliori cure standard.
• Dimostrare la fattibilità del trattamento con Mirtazapina nei diversi paesi europei in termini di accettabilità del trattamento offerto rispetto al trattamento standard dei diversi paesi coinvolti.
• Valutare l'impatto dei pazienti che ricevono Mirtazapina sui caregiver, in particolare le relazioni del caregiver primario (famiglia o amico) sui loro oneri,sulla qualità della vita e sull'esperienza di caregiving e sulle ore totali di cure informali. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All secondary endpoint will de evaluated when all participants have been followed up to completion i.e. 180 days post randomisation. |
| Tutti gli endpoint secondari saranno valutati al termine dell'intervento, ovvero 180 giorni dopo la randomizzazione. |
|
| 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 | 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Ireland |
| Italy |
| Poland |
| United Kingdom |
|
| 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
|
| The end of trial is defined as the date of the final data download for final analysis. |
| La fine della sperimentazione è definita come la data del download finale dei dati per l'analisi statistica. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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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