| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dermatomyositis (DM) |
| Dermatomiosite (DM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Dermatomyositis is a rare and serious autoimmune disease.An over-active immune response causes chronic inflammation,which results in growth of scar tissue in the skin,muscles,and many internal organs. |
| dermatomiosite è una malattia autoimmune rara e graveUna risposta immunitaria eccessivamente attiva provoca infiammazione cronica, che provoca la crescita di tessuto cicatriziale nella pelle,nei mus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012503 |
| E.1.2 | Term | Dermatomyositis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of lenabasum compared to placebo in subjects with dermatomyositis (DM). |
| Valutare l'efficacia di lenabasum rispetto al placebo nei soggetti affetti da dermatomiosite (DM) |
|
| E.2.2 | Secondary objectives of the trial |
| Tp evaluate the safety and tolerability of lenabasum in subjects with DM. |
| Valutare l'efficacia e la tollerabilità di lenabasum nei soggetti affetti da DM |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to understand and voluntarily sign the informed consent
2. Male or female = 18 years of age at the time of signing the informed consent
3. Fulfill one of the following criteria for DM:
a. Bohan and Peter's criteria for probable or definite DM (Bohan and Peter,1975a; Bohan and Peter 1975b)
b. ACR/EULAR criteria (Lundberg et al, 2017)
4. Subject has active DM as determined by the investigator
5. Disease activity/severity fulfils one of the following three criteria:
i. MDGA = 3 cm (0-10 cm scale) and MMT-8 score = 142 (out of 150 total possible)
ii. Sum of MDGA, PtGA and EMGA VAS scores is = 10 cm (all scales individually on 0-10 cm scale)
iii. MDGA = 3 cm and CDASI activity score of >14
6. Stable doses of immunosuppressive medications for DM as defined by:
a. Unchanged dose of oral corticosteroids = 20 mg per day prednisone or equivalent for = 4 weeks before Visit 1
b. Unchanged dose of immunosuppressive medications other than oral corticosteroids for = 8 weeks before Screening
7. Willing to not start or stop any immunosuppressive medications for DM from Screening through end of study, unless a change is part of the protocol or considered in the subject’s best medical interest by the site investigator or another physician who has primary responsibility for treating the subject’s DM.
8. Willing to not use any cannabinoids, including recreational marijuana, medical marijuana and other prescription cannabinoids from Screening through end of study.
9. Able to adhere to the study visit schedule and other protocol requirements and follow study restrictions.
10. Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding and they or their male sexual partner must be using at least one acceptable method of contraception (see Appendix 1) for at least 4 weeks before Visit 1 and be willing to continue its use for at least 4 weeks after discontinuation of study product.
11. Male subjects must be willing to follow acceptable contraceptive requirements (see Appendix 1) and should not get anyone pregnant while they are taking the study product or within 4 weeks after taking the last dose of the study product, during which time period they or their f emale sexual partner must be willing to use at least one recommended
method of contraception. |
1. Capacità di comprendere e firmare volontariamente il consenso informato
2. Uomo o donna maggiore di 18 anni al momento della firma del consenso informato
3. Rispetto di uno dei seguenti criteri per la Dermatomiosite:
a. Criterio di Bohan e Peter’s (Bohan e Peter, 1975a; Bohan e Peter 1975b)
b. Criterio ACR/EULAR ( Lundberg et al, 2017)
4. Il soggetto presenta un a Dermatomiosite attiva determinata dallo Sperimentatore
5. L’attività/gravità della patologia rispetta uno dei seguenti tre criteri:
i. MDGA = 3 cm (scala 0-10 cm) e punteggio MMT-8 = 142 (su totale possibile di
150)
ii.Somma dei punteggi di MDGA, PtGA e EMGA VAS è = 10 cm (all scales individually
on 0- 10 cm scale)
iii. MDGA = 3 cm e punteggio attività CDASI di >14
6. Dosi stabili di farmaci immunosoppressori per la dermatomiosite, come definito:
a. Dose invariata di corticosteroidi = 20 mg al giorno, prednisone oe equivalente for
= 4 settimane prima della Visita 1
b. Dose invariata di farmaci immunosoppressori diversi da corticosteroidi orali per =
8 settimane prima dello Screening
7. Intenzione a non iniziare o interrompere qualsiasi farmaco immunosoppressivo per la
dermatomiosite dallo Screening fino alla fine dello studio, a meno che un cambio sia
parte del protocollo o considerato come miglior interesse medico per il soggetto dallo
Sperimentatore o da altro medico il quale ha responsabilità primaria per il trattamento
della dermatomiosite del soggetto.
8.Intenzione a non usare qualsiasi cannabinoide, compresa marijuana ad uso ricreativo,
marijuana medica e altre prescrizioni di cannabinoidi dallo Screening fino alla fine dello
studio.
9. Capacità di aderire al programma delle visite di studio, ad altri requisiti del protocollo
e seguire le restrizioni dello studio.
10.Le donne in età fertile non devono risultare in stato di gravidanza o allattamento,
devono utilizzare almeno un metodo di contraccezione almeno 4 settimane prima della
visita 1 continuandone l’uso per almeno 4 settimane dopo l’interruzione del prodotto di
studio.
11. I soggetti uomini devono essere disposti a seguire i requisiti di contraccezione e
dovrebbero evitare gravidanze con la partner mentre assumono il farmaco di studio o
entro le 4 settimane dopo aver assunto l’ultima dose del farmaco di studio, durante tale
periodo essi o il proprio partner devono essere disposti ad utilizzare almeno un metodo
di contraccezione. |
|
| E.4 | Principal exclusion criteria |
1. Unstable DM or DM with end-stage organ involvement at Screening or Visit 1, including:
a. On an organ transplantation list or has received an organ transplant, except corneal transplant
b. Interstitial lung disease requiring constant oxygen therapy. This excludes oxygen used to aid sleep or exercise
c. Pulmonary hypertension requiring constant oxygen therapy. This excludes oxygen used to aid sleep or exercise
d. Subjects requiring supplemental tube feeding or parenteral nutrition
2. Certain medications at Visit 1, including:
a. Treatment with intravenous or intramuscular corticosteroids within 4 weeks before Visit 1 (Note: treatment with intra-articular corticosteroids within 4 weeks before Visit 1 is allowed)
b. Treatment with oral or intravenous antibiotics or antiviral treatments for new bacterial or viral infections within 4 weeks of Visit 1. This does not include prophylactic antibiotics or antiviral treatments
c. Any investigational agent within 30 days or 5 therapeutic half-lives of that agent whichever is longer, before Visit 1
3. Significant diseases or conditions other than DM that may influence response to the study product or safety, such as:
a. Acute or chronic hepatitis B or C infection (see Section 8.2.6)
b. Human immunodeficiency virus infection (see Section 8.2.6)
c. History of active tuberculosis or positive tuberculosis test without a completed course of appropriate treatment. Having already completed at least 1 month of appropriate treatment is eligible.
d. Evidence of cancer (except for treated basal or squamous cell carcinoma of the skin or cervical carcinoma in situ) within 3 years of Visit 1
Note: Overlap with features of SSc, systemic lupus erythematosus, Sjogren’s syndrome, or rheumatoid arthritis is allowed if the dominant clinical disease is DM.
4. Any of the following values for laboratory tests at Screening:
a. A positive pregnancy test in women of child-bearing potential (WOCBP) - also at Visit 1
b. Hemoglobin < 9 g/dL in males and < 8 g/dL in females
c. Neutrophils < 1.0 × 10^9/L
d. Platelets < 75 × 10^9/L
e. Creatinine clearance < 50 mL/min/1.73 m2 on screening blood
test, per the Modification of Diet in Renal Disease Study or in 24 hour
urine creatine clearance measurement
5. Any known hypersensitivity to lenabasum or any of its excipients.
6.Any medical, psychiatric or substance abuse condition, concurrent medical therapies, or abnormal laboratory values that in the opinion of the site investigator may put the subject at greater safety risk, influence response to study product, or interfere with study assessments
7. Subjects who have been accommodated in an institution as a result of official or judicial decision. When there is doubt as to subject eligibility, the investigator or qualified designee should discuss a subject's eligibility with the Medical Monitor. |
1. Dermatomiosite instabile o dermatomiosite con interessamento di organo allo stadio
terminale allo Screening o alla Visita 1, compresi:
a. Presenza su lista d’attesa per trapianto o ricezione di trapianto d’organo, eccetto
trapianto di cornea
b. Patologia polmonare interstiziale che richiede una costante ossigenoterapia.
Escluso l’ossigeno utilizzato come aiuto al sonno o per esercizi.
c. Ipertensione polmonare che richiede una costante ossigenoterapia. Escluso
l’ossigeno utilizzato come aiuto al sonno o per esercizi.
d. Soggetti che richiedono sonda gastrica supplementare o nutrizione parentale.
2. Determinati farmaci ala Visita 1, compresi:
a. Trattamento con corticosteroidi intravenosi entro 4 settimane prima della visita 1
(il trattamento con corticosteroidi intra-articolari entro 4 settimane prima della visita
1 è consentito)
b. Trattamento con antibiotici o anti-virali orali o intravenosi per nuove infezioni
batteriche o virali entro 4 settimane dalla visita 1. Questo non include i trattamenti
di profilassi antibiotica o antivirale
c. Eventuali agenti sperimentali entro 30 giorni o 5 emi-vite terapeutiche di tale
agente a seconda di quale sia, prima della visita 1
3. Significanti patologie o altre condizioni oltra alla dermatomiosite che possano
influenzare il responso del prodotto di studio o la sicurezza, come:
a. Infezione da epatite cronica B o C (HBsAg o HCV RNA positivi)
b. Infezione da virus dell’immunodeficienza
c. Precedenti di tubercolosi attiva o test positivo alla tubercolosi senza il
completamento di un appropriato corso di trattamento o avendo già completato
almeno un mese di trattamento appropriato
d. Evidenza di tumore (escluso carcinoma cutaneo trattato basocellulare o a cellule
squamose o carcinoma della cervice uterina in loco) entro 3 anni dalla visita 1.
Nota: Sovrapposizioni con caratteristiche di SSc, lupus sistemico eritematoso, sindrome
di Sjogren, o l’ artrite reumatoide è consentita se la patologia clinica dominante è la
dermatomiosite.
4. Uno dei seguenti valori ai test di laboratorio allo Screening:
a. Testi di gravidanza positivo in donne di età fertile – anche alla visita 1
b. Emoglobina < 9 g/dL per gli uomini e < 8 g/dL per le donne
c. Neutrofili <1.0 × 109/L
d. Piastrine <75 × 109/L
e. Clearance della creatinina < 50 mL/min agli esami del sangue allo Screening, per
modifica della dieta in studio di patologia renale o nella misurazione della clearance
della creatinina nelle urine nelle 24 ore.
5. Significanti patologie o altre condizioni oltre la dermatomiosite o terapie mediche
concorrenti allo Screening o alla Visita 1, compresi precedenti di non compatibilità con
trattamenti medici che possono mettere i soggetti in elevati rischi di sicurezza,
responso influenzato al prodotto di studio o interferenza nelle valutazioni di studio.
6 Soggetti con nota ipersensibilit¿ al lenabasum o ad uno qualsiasi dei suoi
eccipienti. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy EndpointThe Total Improvement Score (TIS) by the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Myositis Response Criteria compared to placebo at Week 52
TIS score is comprised of 6 core set measures:
1. Physician global activity (MDGA)
2. Patient global activity (PtGA)
3. Manual Muscle Testing (MMT)
4. Health Assessment Questionnaire (HAQ)
5. Muscle enzymes
6. Extramuscular global activity (EMGA)
Secondary Efficacy Endpoints
Change from Baseline compared to placebo at Week 52 in:
1. Mean MMT-8 score
2. Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score
3. Proportion of subjects who achieve clear or almost clear skin on the Investigator Global Assessment (IGA) scale of skin activity
4. Short Form – 36 (SF-36) physical functioning domain score
5. Corticosteroid dose
6. Forced Vital Capacity (FVC) % predicted
7. Each Component of the TIS (MDGA, PtGA, HAQ, muscle enzymes, and EMGA)
Tertiary Efficacy Endpoints
Change from Baseline compared to placebo at Week 52 in physician or laboratory assessments:
1. FVC absolute change in mL
2. Proportion of subjects reaching a CDASI activity score of = 14
3. CDASI damage score
4. MDGA (Likert Scale)
Change from Baseline compared to placebo at Week 52 in patient reported outcomes:
1. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score
2. 5-D Itch Score
3. National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Short Form domain scores
4. Patient Visual Analog Scale (VAS) scores of Pain
5. Skindex-29+3
6. European Quality of Life 5-domain (EQ-5D) questionnaire score
7. SF-36 domain scores other than the physical functioning domain score
Proportion of subjects at Week 52:
1. Achieving a TIS of = 20, = 40, and = 60
2. Achieving a reduction in dose of any immunosuppressive medication, among subjects receiving immunosuppressive medications at Baseline
3. Requiring an increase in dose of any immunosuppressive medication, or rescue immunosuppression for (> 2 weeks)
Subset analyses of outcomes above by Baseline characteristics:
1. TIS by: MMT-8 score and other core set measures as continuous variables
2. TIS and core set measures and secondary outcomes by: age (continuous variable); geographic region (US,rest of world); any noncorticosteroid immunosuppressive treatment (yes, no); dose of oral prednisone or equivalent
Minimal Important Difference (MID):
1. Determine MID in TIS, HAQ-DI and CDASI in DM
2. Subset analysis to determine proportion of subjects that achieve MID in TIS, HAQ-DI and CDASI |
TIS secondo i criteri di risposta alla miosite per il 2016 dell'American College of
Rheumatology (ACR)/European League Against Rheumatism (EULAR) rispetto a placebo
alla Settimana 52
Il punteggio TIS è composto da 6 parametri di base:
1.Valutazione globale del medico (Physician Global Assessment, MDGA)
2.Valutazione globale del paziente (Patient Global Assessment, PtGA)
3.Test muscolare manuale (Manual Muscle Testing, MMT)
4.Questionario di valutazione della salute (HAQ)
5.Enzimi muscolari
6.Attività globale extramuscolare (EMGA) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Muscle Enzymes: from Baseline through Week 52;
For others: Day 1, Week 4, Week 16, Week 28, Week 40, Week 52
Secondary
MMT-8 score, CDASI, IGA, SF-36: From Baseline through Day 1, Week 4,
Week 16, Week 28, Week 40, Week 52.
Primary
Corticosteroid dose, Safety monitoring, blood lab safety testing: From
Baseline through Week 52.
Spiromarty (FVC%): From Baseline through Day 1, Week 4, Week 16,
Week 28, Week 52.
TIS (MDGA, PtGA, HAQ, muscle enzymes, EMGA): Muscle Enzymes: from
Baseline through Week 52;
For others: Day 1, Week 4, Week 16, Week 28, Week 40, Week 52
Tertiary
FACIT-Fatigue score, 5-D Itch Questionnaire, PROMIS-29 Short Form,
Patient VAS score for pain, Skindex-29+3 , EQ-5D questionnaire, SF-
36:Day 1, Week 4, Week 16, Week 28, Week 40, Week 52 |
Enzimi muscolari: dal basale alla
settimana 52; Per gli altri: giorno 1, settimana 4, settimana 16, settimana 28,
settimana 40, settimana 52 |
|
| E.5.2 | Secondary end point(s) |
1. Adverse events (AEs)
2. Changes in vital signs, physical examinations, blood and urine laboratory safety tests, and ECGs associated with lenabasum treatment
3. Number of subjects who permanently discontinue study product due to AEs probably- or definitely related to treatment |
Variazione dal basale rispetto a placebo alla Settimana 52 di:
1. Punteggio MMT-8 medio
2. Punteggio dell’attività per l'indice Cutaneous Dermatomyositis Disease Area and
Severity Index (CDASI)
3. Percentuale dei soggetti che conseguono una guari gione completa o quasi
completa della pelle, in base alla scala di valutazione globale dello sperimentatore
(Investigator Global Assessment, IGA) per l'attività cutanea
4. Punteggio del dominio dell'attività fisica per l'indice Short Form –36 (SF-36)
5.Dose di corticosteroidi
6. % prevista della capacità vitale forzata (Forced Vital Capacity, FVC)
Eventi avversi (EA) e alterazioni di: segni vitali, esami obiettivi, test di sicurezza in
laboratorio su sangue e urine, ECG associati al trattamento con lenabasum.
Numero di soggetti che interrompono in modo definitivo l'assunzione del prodotto
dello studio a causa di EA, verosimilmente o sicuramente correlati al trattamento. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AE monitoring From Baseline through Week 52.
ECGs: From Baseline through Day 1, Week 4, Week 28, Week 52.
Urine dipstick: Baseline through Day 1, Week 4, Week 28, Week 52. |
Tempo/i di rilevazione di questo end point: Punteggio MMT-8, CDASI, IGA,
SF-36: dalla baseline al giorno 1, settimana 4, settimana 16, settimana 28,
settimana 40, settimana 52. Farmaci concomitanti (dose di corticosteroidi),
monitoraggio della sicurezza, test di sicurezza della sangue: dalla baseline fino alla
settimana 52.Spiromarty (FVC%): dalla baseline al giorno 1, settimana 4, settimana
16, settimana 28, settimana 52.ECG: dalla baseline al giorno 1, settimana 4,
settimana 28, settimana 10. Stick reattivo alle urine: baseline Giorno 1, Settimana 4,
Settimana 28, Settimana 52. |
|
| 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 | 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 | Yes |
| 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Canada |
| Japan |
| Korea, Republic of |
| United States |
| Bulgaria |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| LVLS |
nel caso si tratti
dell'ultima visita dell'ultimo paziente indicare "LVLS", altrimenti fornire la
definizione: LVLS |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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