| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe plaque psoriasis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037153 |
| E.1.2 | Term | Psoriasis |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this exploratory trial is to evaluate the comparative safety through week 12 of two treatment transition strategies in patients with inadequate response to methotrexate: discontinuation of methotrexate with immediate initiation of ustekinumab versus initiation of ustekinumab with overlap and gradual dose reduction of methotrexate over 4 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
- to evaluate the safety, efficacy, and quality of life associated with ustekinumab through Week 52
- to evaluate the effects of increasing the dose of ustekinumab from 45 mg to 90 mg at Week 28 and/or Week 40 in those patients (≤100 kg) who do not achieve a PASI 75 response at Week 28 and/or Week 40 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Potential patients must satisfy all of the following criteria to be enrolled in the study:
1. 18 years of age or older at time of consent.
2. Diagnosis of plaque-type psoriasis for at least 6 months prior to first administration of study agent (patients with concurrent psoriatic arthritis may be enrolled).
3. Moderate-to-severe psoriasis scored as a PASI ≥10 at screening and at the time of first administration of ustekinumab.
4. Currently receiving (and have been receiving for at least 8 continuous weeks prior to screening) systemic therapy with methotrexate at an effective dose of at least ≥ 10 mg/week ≤25 mg/week, with an inadequate response to this treatment (due to either efficacy or tolerability) and, in the judgment of the treating physician and patient, a treatment change is needed.
5. Women of childbearing potential must be using adequate birth control measures throughout the study (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilisation). Women must agree to continue to use such birth control measures and not become pregnant or plan to become pregnant for at least 15 weeks after receiving the last dose of ustekinumab, and for at least 6 months after receiving the last dose of methotrexate. Breastfeeding is also not permitted throughout the study and for at least 15 weeks after the last dose of ustekinumab. All women of childbearing potential will undergo pregnancy testing before and during therapy (non-childbearing potential is defined as post menopausal for at least 1 year or surgical sterilisation or hysterectomy at least 3 months before study start).
6. Men must be using adequate birth control measures whilst receiving methotrexate, and for 6 months after the last dose of methotrexate.
7. Willing/able to adhere to the prohibitions and restrictions specified in this protocol.
8. Capable of giving informed consent; consent must be obtained in writing prior to any study related procedures.
9. Must agree not to receive a live virus or live bacterial vaccination during the study or for at least 15 weeks after last dose of study agent.
10. Must agree not to receive a Bacille Calmette-Guerin (BCG) vaccination during the study or up to 12 months after the last study agent injection.
11. Healthy on the basis of physical examination, medical history, and vital signs, performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population.
12. Screening laboratory test results within the following parameters:
Haemoglobin ≥ 10 g/dL
White blood cells ≥ 3.5 x 109/L
Neutrophils ≥ 1.5 x 109/L
Platelets ≥ 100 x 109/L
Serum creatinine ≤ 1.5 mg/dL (or ≤ 133 mol/L)
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase levels must not exceed two times the upper limit of the normal range for the laboratory conducting the test.
13. Eligible according to the following tuberculosis (TB) screening criteria:
a. No signs or symptoms suggestive of active TB upon medical history and/or physical examination.
b. No history of active or latent TB.
c. No recent close contact with a person with active TB.
d. Within 6 weeks prior to the first administration of study agent, have a negative TB test using EITHER a tuberculin skin test OR the QuantiFERON-TB Gold test (Attachment 2). TB testing should be interpreted using criteria for immunocompromised patients. Sequential testing whereby a positive tuberculin skin test is followed by a QuantiFERON-TB Gold test is not permitted.
e. Patients diagnosed with active or latent tuberculosis infection during screening should be excluded from the study. Subjects with a newly identified positive tuberculin skin test, or a positive or indeterminate QuantiFERON-TB Gold test result, must be excluded from the study and referred to an appropriate specialist for follow-up. An indeterminate Quantiferon test may be repeated for confirmation of the result provided the result is obtained within the screening period. If the test is indeterminate on the retest the patient must be excluded from the study.
f. Have a chest radiograph (posterior-anterior view) taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of currently active TB or old inactive TB. |
|
| E.4 | Principal exclusion criteria |
Potential patients who meet any of the following criteria will be excluded from participating in the study:
1. Currently have non-plaque forms of psoriasis.
2. Currently receiving ciclosporin, fumarates, PUVA, etanercept, efalizumab, infliximab, adalimumab or alefacept.
3. Currently receiving any other systemic treatment (except methotrexate) that may improve psoriasis.
4. Currently receiving any other biologic agent.
5. Have received biologic therapy within the past 12 weeks or 5 half-lives of the agent, whichever is greater.
6. Have received natalizumab, efalizumab, or agents that deplete B or T cells within 12 months of screening, or, if after receiving these agents, evidence is available at screening of persistent depletion of the targeted lymphocyte population.
7. Have used any investigational drug within the previous 4 weeks or 5 half-lives of the investigational agent, whichever is longer.
8. Have received phototherapy or any systemic medications/treatments (except methotrexate) that could affect psoriasis or PASI evaluation within 2 weeks or 5 half-lives (whichever is longer) of the first ustekinumab injection.
9. Have received any topical treatments for psoriasis within 2 weeks or 5 half-lives (whichever is longer) of the first ustekinumab injection.
10. Have current drug-induced psoriasis
11. Pregnant, breastfeeding, or planning pregnancy while enrolled in the study.
12. Have previously failed treatment with any therapeutic agent directly targeted at reducing IL-12 or IL-23, including, but not limited to, ustekinumab and ABT-874 (briakinumab).
13. Are currently receiving lithium, antimalarials, or intramuscular gold or have received lithium, antimalarials, or intramuscular gold within 4 weeks of the first administration of study agent.
14. Have received, within 2 weeks prior to the first dose of ustekinumab, a live virus or bacterial vaccination. Patients must agree not to receive a live virus or bacterial vaccination during the study and for at least 15 weeks after the last dose of study agent.
15. Have received, or are expected to receive, a BCG vaccination within the 12 months prior screening, during the study, or within 12 months after the last administration of study agent.
16. Diagnosed with active or latent TB infection during screening.
17. Suffer from chronic or recurrent infectious disease, including but not limited to chronic renal infection; chronic chest infection; recurrent urinary tract infection (recurrent pyelonephritis or chronic nonremitting cystitis); or open, draining, or infected skin wounds or ulcers.
18. Have had or have a serious infection, or have been hospitalised or received IV antibiotics for an infection during the 2- month period prior to screening.
19. Have evidence of current active infection, including TB, or a nodule suspicious for lung malignancy on screening or any other available chest radiograph, unless definitively resolved surgically or by additional imaging and with source document confirmation.
20. Known to be infected with human immunodeficiency virus, hepatitis B, or hepatitis C.
21. Have previously had or have a nontuberculous mycobacterial infection or opportunistic infection
22. Have current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease.
23. Have a transplanted organ (with exception of a corneal transplant in situ for >3 months prior to the first administration of study agent).
24. Have a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
25. Have any known malignancy or have a history of malignancy.
26. Have a known hypersensitivity to ustekinumab or any of its excipients.
27. Are unable or unwilling to undergo multiple venipunctures for laboratory analysis because of poor tolerability or lack of easy access to veins.
28. Are known to have had an illicit substance abuse problem or alcohol dependency within the previous 12 months.
29. Are participating in another study using an investigational agent, procedure, or medical device during participation in this study.
30. Have any condition that, in the opinion of the investigator, would compromise the well being of the patient or the study.
31. Are employees of the investigator or study centre, with direct involvement in the proposed study or other studies conducted under the direction of the study investigator or study centre, or are family members of an employee or investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the proportion of patients experiencing one or more treatment emergent AEs through Week 12 in each treatment arm. Comparisons between arms will be descriptive only. |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality-of-life assessments, immunological markers, protein expression measurements |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| comparison with currently prescriped medication (MTX) |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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