E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
an inflammatory disease of blood vessels |
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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 |
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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). |
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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. |
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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
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 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 at least one of the following:
d) Active GCA within 6 weeks of Day 0 defined as clinical sign/symptom(s) and Westergren ESR> 30 mm/hour or CRP ≥ 1 mg/ dL OR
e) No remission since the diagnosis of disease as per clinical expectations (refractory nonremitting)
4. Remission of GCA at Day 0 (resolution of GCA symptom(s) and CRP < 1.0 or ESR < 20 mm in the first hour), such that the subject can safely participate in the study and follow the protocol defined rocedures, 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 stable or decreasing with the intention to discontinue use 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 having agreed to use an effective method of contraception (i.e., hormonal contraceptives, intrauterine device (IUD), or double barrier methods such as condom plus diaphragm or diaphragm plus spermicide or condom plus spermicide) from Screening visit until 12 weeks after final study drug dministration
10. Male subjects must have documented vasectomy or must agree to use double barrier methods of contraception (such as condom plus diaphragm or diaphragm plus spermicide or condom plus spermicide) or use condom plus hormonal contraceptives or condom plus IUD with their partners of childbearing potential from Day 0 until the Safety Follow-up visit. Male subjects must agree to refrain from donating sperm from Day 0 until the Safety Follow-up visit. |
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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 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 biologic 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 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, 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. Active, untreated or partially treated latent tuberculosis (TB)
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 (20 years for breast cancer) 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) performed within 12 weeks prior to Day 0. The subjects 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time from start of double-blind treatment until the first flare occurring within the first 26-weeks of the double-blind period |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Appro. 18 months after the start of the study |
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E.5.2 | Secondary end point(s) |
Time from start of double-blind treatment until the first flare occurring within the double-blind period
Percentage of subjects at Week 26 with normal ESR
Percentage of subjects at the end of double-blind period with normal ESR
Percentage of subjects at Week 26 with normal CRP
Percentage of subjects at the end of double-blind period with normal CRP
Time to steroid dose of zero
Cumulative steroid dose at Week 26 and at the end of the double-blind treatment period
Change in clinical GCA assessments (including NRS and FACIT) over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Appro. 18 months after the start of the study |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
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 |