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 |
an inflammatory disease of blood vessels |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018250 |
E.1.2 | Term | Giant cell arteritis |
E.1.2 | System Organ Class | 100000004866 |
|
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 |
The primary objective of the study is to evaluate the efficacy of KPL-301 versus placebo, coadministered with a 26-week steroid taper, for maintaining sustained remission for 26 weeks in subjects with newonset or relapsing/refractory giant cell arteritis (GCA). |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study, in subjects with new-onset and relapsing/refractory GCA, are:
a) To evaluate the effect of KPL-301 vs placebo on cumulative corticosteroid dose.
b) To evaluate the effect of KPL-301 vs placebo on health-related quality of life (HRQoL).
c) To evaluate the safety and tolerability of KPL-301.
d) To evaluate the pharmacokinetics (PK) of KPL-301. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Able and willing to provide written informed consent and to comply
with the study protocol
2. Age of ≥ 50 to 85 inclusive
3. Diagnosis of new-onset or relapsing GCA classified according to the
following criteria:
New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, defined as:
a) Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/dL
b) AND at least one of the following:
i. Unequivocal cranial symptoms of GCA (new-onset localized headache,
scalp or temporal artery pain or tenderness, ischemia-related vision loss,
or otherwise unexplained mouth or jaw pain upon mastication)
ii. Unequivocal extracranial symptoms of GCA such as claudication of the
extremities
iii. Symptoms of PMR, defined as shoulder and/or hip girdle pain
associated with inflammatory morning stiffness
c) AND at least one of the following:
i. TAB or ultrasound revealing features of GCA
ii. Evidence of large-vessel vasculitis by angiography or cross-sectional
imaging study such as MRI, CT/CTA, or PET-CT of the aorta or other
great vessels
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND:
Active GCA within 6 weeks of Day 0 defined as clinical sign/symptom(s)
as per above and Westergren ESR> 30 mm/hour or CRP ≥ 1 mg/ dL
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 0 AND
No remission since the diagnosis of disease as per clinical expectations.
i.e. Presence of sign/symptoms as per above and Westergren
ESR>30mm/hour or CRP ≥ 1 mg/ dL within 6 weeks of Day 0
4. Remission of GCA at or before Day 0 (resolution of GCA symptom(s)
and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour), such that the
subject can safely participate in the study and follow the protocol
defined procedures, including initiation of the prednisone taper at the
protocol-specified starting dose (i.e., ≤60 mg/day)
5. At Day 0, receiving or able to receive oral prednisone up to 60 mg/day
for the treatment of GCA
6. If using methotrexate (MTX), oral or parenteral up to 25mg/week is
permitted in screening if started more than 6 weeks prior to Day 0 and
should be tapered to zero by Day 0.
7. Willing to receive antiplatelet therapy depending on the Investigator's
decision
8. Willing to receive treatment for prevention of corticosteroid-induced
osteopenia/osteoporosis depending on the Investigator's decision
9. Female subjects must be:
a) postmenopausal, defined as at least 12 months post cessation of
menses (without an alternative medical cause), or
b) permanently sterile following documented hysterectomy, bilateral
salpingectomy, bilateral ophorectomy, or tubal ligation or having a male
partner with vasectomy as affirmed by the subject, or
c) nonpregnant, nonlactating, and if sexually active having agreed to use
a highly effective method of contraception (i.e., hormonal contraceptives
associated with inhibition of ovulation or intrauterine device [IUD], or
intrauterine hormone-releasing system [IUS], or sexual abstinence)
from Screening visit until the final Washout Safety Follow-up visit 84 ± 3
days from EOT Visit.
10. Male subjects must have documented vasectomy or if sexually active
must agree to use a highly effective method of contraception with their
partners of childbearing potential (i.e., hormonal contraceptives
associated with the inhibition of ovulation or intrauterine device [IUD],
or intrauterine hormone-releasing system [IUS], or sexual abstinence)
from Day 0 until the final Washout Safety Follow-up visit 84± 3 days
from EOT Visit. Male subjects must agree to refrain from donating sperm
during this time period. |
|
E.4 | Principal exclusion criteria |
General Exclusion Criteria
1. Major surgery within 8 weeks prior to Screening or planned major
surgery within 12 months after randomization
2. Transplanted organs (except corneal transplant performed more than
3 months prior to randomization)
3. Major ischemic event unrelated to GCA within 12 weeks of Screening
Exclusions Related to Prior or Concomitant Therapy
4. Concurrent enrollment in another clinical study, with the exception of
observational studies
5. Previous treatment with KPL-301
6. Treatment with any non-biologic investigational drug therapy within 4
weeks or 5 half-lives of the study agent, whichever was longer, prior to
Screening
7. Any cell-depleting biological therapies (e.g., anti-CD20) within 12
months prior to Day 0; or previous treatment with noncell-depleting
biological therapies (such as anti-tumor necrosis factor [TNF], anakinra,
anti-Interleukin [IL]-6 receptor [e.g. tocilizumab], or abatacept) within
8 weeks (or 5 half-lives, whichever is longer) prior to Screening
8. Treatment with alkylating agents within 12 weeks prior to Screening
9. Intramuscular, IV corticosteroids, Intra-articular corticosteroids
within 4 weeks prior to Screening
10. Receipt of live (attenuated) vaccine within the 4 weeks before Day 0
11. Treatment with hydroxychloroquine, cyclosporine A, azathioprine,
cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks of
Screening Relating to Medical History
12. Female subjects who are pregnant, intending to become pregnant, or
are breastfeeding
13. Any condition that, in the opinion of the Investigator, could interfere
with evaluation of KPL-301 or interpretation of subject safety or
confound the results of the study
14. Known history of allergy or reaction to any component of the KPL-
301 or placebo formulation or to any other biologic therapy or
prednisone or any of its excipients
15. Positive (or 2 indeterminate) QuantiFERON test results.
16. Clinically significant active infection including signs/symptoms
suggestive of infection, any significant recurrent or chronic infection
(including positive hepatitis C virus antibody [HCVAb]), or any episode
of infection requiring hospitalization or treatment with IV antibiotics
within 12 weeks before Screening. Subjects with any opportunistic
infection within 6 months before Screening will be excluded from the
study.
17. Subjects with chronic active hepatitis B infection as defined below
will be excluded from the study:
Hepatitis B surface antigen (HbsAg) positive
Hepatitis B anti-core antibody positive but anti-surface antibody
negative
18. Subjects at a high risk of infection (e.g., history of hereditary or
acquired immune deficiency disorder including a history of known
human immunodeficiency virus [HIV] infection), a history of an infected
joint prosthesis at any time with that prosthesis still in situ, leg ulcers,
indwelling urinary catheter, or persistent or recurrent chest infections
19. History of cancer within the last 10 years - except for basal and
squamous cell carcinoma of the skin or in situ carcinoma of the cervix
treated and considered cured
20. Evidence of clinically uncontrolled respiratory disease. The
Investigator should review the data from subjects' respiratory
assessments including chest x-ray and pulmonary function tests (PFTs)
including DLCO performed during the screening period or within 12
weeks prior to Day 0 if results of prior assessments are available.
Available PFT and DLCO assessments must have had values ≥ 60% of
predicted for measurements performed and no uncontrolled lung
disease. A subject's medical regimen should not have been significantly
intensified to control lung disease within 12 weeks prior to Day 0.
21. History of chronic respiratory tract infections
22. Congestive heart failure of New York Heart Association classification
III or IV
23. At screening blood tests, any of the following:
a) Aspartate transaminase (AST) > 2 × upper limit of normal (ULN)
b) Alanine transaminase (ALT) > 2 × ULN
c) Hemoglobin < 75 g/L
d) Neutrophils < 1.5 × 109/L
e) Creatinine clearance (CrCl) <30 mL/min |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Time to flare by week 26 defined as time from randomization to the first
flare occurring within the treatment period |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Appro. 32 weeks after the start of the study |
|
E.5.2 | Secondary end point(s) |
• Sustained remission rate at Week 26
• Percentage of subjects who have completed the corticosteroid taper and who have a normal ESR by week 26
• Percentage of subjects who have completed the corticosteroid taper and who have a normal CRP by Week 26
• Percentage of subjects who completed the corticosteroid taper and who have no signs/symptoms of GCA nor new or worsening vasculitis by imaging by Week 26
• Time to elevated ESR by week 26
• Time to elevated CPR by week 26
• Time to signs/symptoms of GCA or new or worsening vasculitis by week 26
• Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up Period
• Change in clinical GCA assessments (including NRS and FACIT) over time
• Change in quality-of-life (EO-5D and SF-36) over time |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Appro. 44 weeks after the start of the study |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | 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 | 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 | 36 |
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 |
Australia |
Belgium |
Croatia |
Estonia |
Germany |
Ireland |
Italy |
Netherlands |
New Zealand |
Poland |
Serbia |
Slovenia |
Spain |
United Kingdom |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |