| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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. |
|
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of lenabasum in subjects with 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
female sexual partner must be willing to use at least one recommended
method of contraception.
|
|
| 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
Total Improvement Score (TIS) by the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Myositis Response Criteria at Week 28
The TIS is comprised of 6 core set measures and absolute value and change from baseline in each core set measure will be presented to support the composite TIS:
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)
A MMT that assesses strength in 8 muscle groups (MMT-8) will be used in this study.
Secondary Efficacy Endpoints
The following endpoints will be compared in lenabasum 20 mg BID and placebo cohorts and lenabasum 5 mg BID and placebo cohorts at Week 28, unless otherwise specified. All outcomes involving continuous variables will be assessed as absolute values and, if relevant, change from Baseline. All categorical variables will be assessed as number and proportion of subjects in each category:
1. Subjects who achieve Definition of Improvement (DOI), defined as ≥ 3 of 6 core set measures improved by ≥ 20% (relative to Baseline) with no more than 2 core set measures worsening by ≥ 25% (MMT-8 may not decrease by ≥ 25% from baseline)
2. Subjects who improve by at least one category on the Investigator Global Assessment (IGA) scale of skin activity
3. Subjects who achieve TIS ≥ 40 (at least moderate improvement)
4. TIS in subjects receiving any immunosuppressant medication for > 1 year at Baseline
5. TIS at Visit 10 (Week 52)
6. Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score
Tertiary Efficacy Endpoints
These endpoints will be assessed at all visits at which they are measured, if not already included as the primary or secondary efficacy endpoints. Additional tertiary efficacy endpoints may be included in the Statistical Analysis Plan (SAP).
Change from Baseline compared to placebo in physician or laboratory assessments:
1.Forced vital capacity (FVC) absolute change in mL and percent predicted
2.CDASI damage score
3.MDGA (Likert Scale)
4.Corticosteroid dose
Change from Baseline compared to placebo 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
Proportion of subjects:
1.Achieving a CDASI activity score of ≤14
2.Achieving clear or almost clear skin on the IGA scale of skin activity
3.Achieving a TIS of ≥20, ≥ 40, and ≥ 60
4.Achieving a reduction in dose of any immunosuppressive medication (including corticosteroid) for > 28 days, among subjects receiving immunosuppressive medications at Baseline
5.Requiring an increase in dose of any immunosuppressive medication (including corticosteroids), or rescue immunosuppression for > 28 days
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, ex-US); any non-corticosteroid 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
|
|
| 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.
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 |
|
| 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 |
|
| 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. |
|
| 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 | 3 |
| 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 | No |
| 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 |
| Spain |
| Sweden |
| 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
|
|
| 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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