| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Autoimmune Disorders Polymyositis and Dermatomyositis |
|
| E.1.1.1 | Medical condition in easily understood language |
| inflammation of the muscles; inflammation of the skin |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10003816 |
| E.1.2 | Term | Autoimmune disorders |
| E.1.2 | System Organ Class | 10021428 - Immune system 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 |
| Evaluate efficacy of KZR-616 in patient with Polymyositis or Dermatomyositis |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objective(s)
Evaluate safety and tolerability of KZR-616 in patients with PM or DM
Evaluate pharmacokinetics (PK) of KZR-616 in patients with PM or DM.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult patients at least 18 years of age at the time of signing informed consent at Screening
2. Body Mass Index (BMI) of 18 to 40 kg/m x m
3. Diagnosis of probable or definite DM or PM by the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria
4. Must have their data reviewed by an adjudication committee to confirm eligibility unless at least 1 of the
following is present:
a. Muscle biopsy with evidence of active myositis within the last 6 months prior to or at Screening
b. Electromyography or magnetic resonance imaging (MRI) with evidence of active myositis within the last 6 months prior to Screening
c. A CK ≥4 × upper limit of normal (ULN).
5. Must have demonstrable muscle weakness as measured by the MMT-8 with a score ≥80/150 but ≤136/150 units and any 2 of the following:
a. MDGA visual analog scale (VAS) ≥2 cm
b. PtGADA VAS ≥2 cm
c. At least one muscle enzyme laboratory measurement (ie, CK, aldolase, LDH) ≥1.3 × ULN
d. MDAAT Extramuscular Global Activity VAS ≥1 cm.
6. Documented inadequate response to a 12-week trial of corticosteroids or at least 1 immunosuppressant
(eg, methotrexate [MTX], mycophenolate mofetil [MMF], mycophenolate sodium [MPS], azathioprine
[AZA], leflunomide [LEF], tacrolimus, cyclosporine [CyA]) OR have demonstrated significant
documented toxicity or intolerance to such therapies
7. Has had age-appropriate cancer screening that is up to date and negative for evidence of malignancy as
per local standard of care
8. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and must agree to employ adequate birth control measures for the duration of the study.
Women of childbearing potential (WOCBP) must use highly effective and medically acceptable methods of contraception to prevent pregnancy during Screening and must agree to continue to practice
adequate contraception during the study and for 4 weeks after administration of the last dose of the studydrug.
For the purposes of this study, WOCBP are defined as: all postpubescent female patients, unless the
patient is postmenopausal (defined by amenorrhea for at least 2 years or amenorrhea for at least 1 year with confirmatory follicle stimulating hormone [FSH] level in the postmenopausal range as documented historically or measured by the central laboratory at Screening and if patient is not on supplementary
hormonal therapy) or if the patient is surgically sterile (ie, tubal ligation, hysterectomy, bilateral salpingoophorectomy).
Highly effective contraception is defined as the use of 2 barrier methods (eg, female diaphragm and
male condom), 1 barrier method with spermicide, intrauterine
device, or hormonal contraceptives
(eg, implant or oral). If using a hormonal form of contraception, it must have been stable for at least 4 weeks prior to Screening, and if using concomitant mycophenolate, the patient must use another
nonhormonal form of highly effective contraception. Abstinence will be acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation) and
withdrawal are not acceptable methods of contraception
9. Male patients must be either congenitally sterile or surgically sterile (vasectomy with documented confirmation of aspermia) or willing to use a condom in addition to having their female partner use another form of contraception (such as an intrauterine device, barrier method with spermicide, or hormonal contraceptive [eg, implant, injectable, patch, or oral]) from Screening until 12 weeks after the last dose of study drug, unless their partners are infertile or surgically sterile
10. Willing and able to comply with the requirements of the protocol
11. Provide written informed consent prior to any study-related procedure.
|
|
| E.4 | Principal exclusion criteria |
1. Has significant muscle damage (eg, severe muscle atrophy, end-stage disease, postmyopathic DM) per Investigator opinion or has a muscle damage VAS score ≥5 cm on the MDI
2. Any other form of myositis or myopathy other than PM or DM (eg, metabolic or drug-induced myopathy, drug-induced myositis, juvenile PM or DM, inclusion body myositis, cancer-associated myositis [myositis diagnosed within 3 years, either before or after, of a diagnosis of any malignancy except for squamous or basal cell carcinoma of the skin or cervical carcinoma in situ], myositis in
overlap with another connective disease [eg, systemic lupus erythematosus{SLE}, systemic sclerosis,
rheumatoid arthritis {RA}], or muscular dystrophy); patients with secondary Sjogren’s syndrome, necrotizing myopathy, or antisynthetase syndrome are permitted to participate in this study
3. Any condition (eg, severe arthritis with limited range of motion or severe calcinosis) that, in the Investigator’s opinion, precludes the ability to quantitate muscle strength
4. Has severe interstitial lung disease per Investigator opinion or has a pulmonary damage VAS score ≥5 cm on the MDI
5. Presence of autoinflammatory disease (eg, psoriatic arthritis, axial spondyloarthropathy, inflammatory bowel disease)
6. Has received treatment with any of the following:
a. Oral prednisone (or prednisone equivalent) >20 mg/day at Screening or during the Screening Period, or initiation of oral prednisone during the Screening Period. If oral prednisone is being
used at Screening, use should be stable during the 2 weeks prior to Baseline
b. Use of nonsteroidal immunosuppressants other than oral MMF or MPS (≤3 g/day or 2160 mg/day, respectively); oral, intramuscular (IM), or SC MTX (≤25 mg/week); AZA (≤2.5 mg/kg/day); LEF (≤20 mg/day); tacrolimus (≤3 g/day); or concurrent use of more than 1
nonsteroidal immunosuppressant at Baseline. If a permitted nonsteroidal immunosuppressant is being used, it must have used for at least 12 weeks and must have been taken at a stable dose (including stable route of administration) for the last 4 weeks prior to Screening. If MMF, MPS, MTX, AZA, LEF, or tacrolimus is being discontinued, it must be discontinued at least 4 weeks prior to Baseline
c. Antimalarials exceeding the recommended doses (hydroxychloroquine up to 400 mg/day or
6.5 mg/kg/day, whichever is less; chloroquine up to 250 mg/day, or quinacrine up to
100 mg/day are permitted) or taken at an unstable dose during the 12 weeks prior to Screening. If an antimalarial is being discontinued, it must be discontinued at least 4 weeks prior to
Baseline. Antimalarials are considered distinct from corticosteroids in (a) and nonsteroidal immunosuppressants in (b) above
d. Initiation of or use of an unstable dose of topical therapy (eg, corticosteroids, pimecrolimus) in the 4 weeks prior to Screening. If topical therapy is being discontinued, it must be discontinued
at least 4 weeks prior to Baseline.
7. Receipt of any of the following treatments within the following timeframes before Screening:
a. Oral corticosteroids at doses ≥1 mg/kg/day prednisone or equivalent: 4 weeks
b. Intravenous or IM corticosteroids: 4 weeks
c. Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks
d. Intravenous, SC, or IM Ig: 4 weeks
e. Cyclophosphamide or chlorambucil: 24 weeks
f. Prohibited nonbiologic nonsteroidal immunosuppressants or targeted therapies including, but
not limited to, CyA, dapsone, tofacitinib, baricitinib: 8 weeks
g. Cytokine or integrin antagonists or selective costimulation modulators including, but not
limited to, interleukin (IL)-1, IL-6, IL-17, IL-12/23, IL-23, interferon (IFN), integrin, and
tumor necrosis factor (TNF)α antagonists or abatacept: 12 weeks
h. B cell-depleting or -modulating therapies (eg, rituximab, ofatumumab, obinutuzumab,
ocrelizumab, belimumab, atacicept): 24 weeks
For those patients who have used an anti-cluster of differentiation (CD) 20 drug at ≥24 weeks
and <48 weeks before Screening, they must have levels of circulating CD19+ B cells ≥the
lower limit of normal (LLN). A CD19 count is not required for patients with prior use of an
anti-CD20 drug ≥48 weeks prior to Screening
i. Previous treatment with the following cell-depleting therapies, including investigational agents
or approved therapies: alemtuzumab, anti-CD4, anti-CD5, or anti-CD3: at any time
j. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer
k. Transfusion with blood, packed red blood cells, or platelets or treatment with plasmapheresis or
plasma exchange: 6 weeks
l. Creatine dietary supplements: 4 weeks.
Nota Bene: Exclusion Criteria eight to nineteen could not be added due to confinement of 5000 characters. All exclusion criteria are listed in the protocol (01Mar19) from page 8-9.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is:
Mean change from start to end of KZR-616 treatment in the Total Improvement Score (TIS), which
ranges from 0 to 100.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis period is from start to end of KZR-616 treatment for both sequence arms combined. A secondary analysis comparing KZR-616 to parallel placebo will be confined to the Baseline to Week 16 period.
Lastly, the usual crossover analysis comparing placebo to KZR-616 will be carried out as an exploratory analysis approach. The rationale for this priority order is as follows. The usual crossover analysis for this design is prespecified as exploratory since it is unknown whether that analysis would be confounded by carryover effect.
In order to maximize the precision for assessment of KZR-616 effect, it is assessed primarily via all patients start to end of KZR-616 treatment, and secondarily by the Treatment Period 1 between-treatment comparison.
|
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints are:
Proportion of patients with an increase ≥20 points on the TIS from start to end of KZR-616 treatment.
The categories and ranges of scores for improvement are: 20-39 points being minimal improvement, 40-59 points being moderate improvement, and ≥60 points being major improvement
Proportion of patients from start to end of KZR-616 treatment meeting IMACS Definition of Improvement (DOI). The IMACS DOI is ≥20% improvement in at least 3 of 6 core set activity measures, with no more than 2 core set activity measures (CSAMs) worsening by ≥25% (the MMT-8 cannot be a worsening measure)
Absolute change and percent change from start to end of KZR-616 treatment in the IMACS individual CSAMs
For patients with DM, the mean change from start to end of KZR-616 treatment in the CDASI
For patients with DM, the mean change from start to end of KZR-616 treatment in the Peak Pruritus NRS.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Start to end of KZR-616 treatment. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| Czechia |
| Germany |
| Hungary |
| Poland |
| United States |
|
| 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 | 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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