| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with moderate to severe rheumatoid arthritis (RA) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10039075 |
| E.1.2 | Term | Rheumatoid arthritis and associated conditions |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 the study is to demonstrate the efficacy of Z102 2.7/360 versus placebo on the Disease Activity Score 28 C-reactive protein (DAS28-CRP) in patients with RA at the study endpoint of 12 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
• Demonstrate the clinical efficacy of Z102 2.7/360 versus the separate components of Z102 (2.7 mg prednisolone and360 mg dipyridamole) and versus 5 mg prednisone, as measured by the DAS28-CRP score, in patients with RA at the study endpoint of 12 weeks
• Examine the efficacy ofZ102versus its separate components on the secondary outcome measures and assessment tools
oDAS28-CRP
oDAS28-CRP individual components
Tender Joint Count
Swollen Joint Count
Patient Global Assessment of Disease Activity
CRP
oAmerican College of Rheumatology ACR20, ACR50, ACR70, which includes
Tender Joint Count
Swollen Joint Count
Patient Global Assessment of Disease Activity
Physician Global Assessment of Disease Activity
Health Assessment Questionnaire
Patient Pain Visual Analog Scale
oMultidimensional Assessment of Fatigue
oTime to failure addition of a disease modifying anti-rheumatic drug or withdrawal due to flare |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1.Prior to screening have voluntarily signed the informed consent form.
2.At Screening be at least 18 years of age.
3.At screening meet the ACR / EULAR criteria for classification of RA(please refer to Section 5.13.2 and/or Appendix B [Section 12.2] for additional details)which include:
o Joint involvement
o Serology
o Acute-phase reactants
o Duration of symptoms
4. At screening have moderate to severe RA, defined as involving a minimum (≥6 total swollen and ≥6 total tender) of the 28 joints assessed.
5. At screening have screening CRP levels of at least 0.6 mg/dl and a DAS28-CRP score ≥4.5.Retesting of the CRP and recalculation of DAS28-CRP (due to CRP <0.6 mg/dL) is allowed one time.
6. Have been on DMARD therapy for at least 90 days, have been on stable DMARD dose without dosage adjustment or modification for 6 weeks, and should be able to maintain the same dose of conventional DMARD therapy during study participation (with or without glucocorticoid therapy). Stable DMARD therapy may include a combination of DMARD agents (methotrexate and azsulfadine or methotrexate and hydroxychloroquine as examples).
7. At screening female patients of childbearing potential (18 to 55 years of age, inclusive) must have negative urinary BhCG tests at enrollment and study completion.
8. Female patients of childbearing potential (18 to 55 years of age, inclusive) must use acceptable methods of birth control (including, but not limited to, IUD, oral or injectable contraceptives, or barrier methods) while in the study.
9. If currently taking the following medications she/he has been on a stable dose of the same drug for at least 3 months prior to entering into the trial and will continue on the same dose for the duration of the trial: statins, diuretics, thyroid hormone, hypoglycemic medications, and cardiovascular medications.
|
|
| E.4 | Principal exclusion criteria |
1.Female patient is pregnant,actating,or of child bearing potential not using acceptable methods of birth control including,but not limited to,IUD,oral or injectable contraceptives,barrier methods or abstinence
2.Patients who do not respond to therapies that include a dose < 10mg prednisone and either a DMARD combination,DMARDbiologic combination or biologics alone
3.Active cardiovascular disease,unless well controlled by appropriate treatment for a minimum of 3months prior to screening
4. taking aspirin for reasons other than for cardiovascular prophylaxis or their total daily dose is greater than 325mg
5.Taking oral steroids at a daily prednisone dose,or the equivalent,of >10mg/day within the past 2weeks
6.Intraarticular,intramuscular,or intravenous glucocorticoids must not have been given at least 6weeks prior to entering the study or be anticipated to be given at any time during the study
7.The need to continue the use of one or multiple NSAIDs at the same time,or the use of acetaminophen on a chronic basis.
Ataminophen/paracetamol will be permitted episodically for pain during the trial,not exceeding 1.5gper day for any 3days in any 7day interval.There are no exclusions during the 30day followup period
8.All opiate use is prohibited.Such agents include oxycodone,
hydrocodone,codeine,morphine sulfate,Demerol(meperidine/pethidine),Dilaudid(hydromorphone),combi
nation products including Percocet(oxycodone and
acetaminophen),Hydrocet(dihydrocodeine
andacetaminophen),Tylenol(acetaminophen or paracetamol) with
codeine,Vicodin(hydrocodone and acetaminophen),Lorcet(hydrocodone and acetaminophen),Lortabs(hydrocodone and acetaminophen)and extended-release formulations
9.Use of any other medications or herbs or non pharmacological
treatments eg acupuncutre used for the treatment of pain is prohibited
10.Excluded medications include Drugs known to interact with dipyridamole(egadenosine, cholinsterase inhibitors,theophylline,caffeine and other xanthine derivatives)or with prednisolone(eganticoagulants,antifungals and HIV protease
inhibitors)Systemic anticoagulants,including
dipyridamole,Coumadin(warfarin),clopidogrel,ticlopidine and aspirin
exceeding 325mg/day(whether or not taken for cardiovascular
prophylaxis) All Systemic antifungal agents, including but not limited to the polyene macrolides(amphotericin B),the
azoles(ketoconazole,miconazole,itraconazole and fluconazole) and the allylamines(terbinafine) All antiHIV drugs belonging to the following classes:members of the nucleoside/nucleotide reverse transcriptase inhibitors,nonnucleoside/
nucleotide reverse transcriptase inhibitors,protease
inhibitors,fusion and entry inhibitors and integrin inhibitors.These
agents include but are not limited to abacavir,zidovudine,didanosine,tenofovir and efavirenz
11.Has,or has had,any active severe infections,such as
osteomyelitis,sepsis,active infectious hepatitis,endocarditis, systemic fungal infection or recent invasive surgical procedures within 30days of study initiation
12.Tuberculosis At screening patients with a history of or currently active tuberculosis as per specific country guidelines are excluded Patients with a positive Chest XRay eg apical thickening compatible with TB exposure/latency are excluded
Patients who have a positive PPD test, in association with compatible signs and symptoms and/or a positive or indeterminate QFT are excluded Note:A patient with a previous positive PPD test is at risk for development of a severe local reaction upon re-exposure.A patient with an established positive PPD result will not be re-challenged,but will
undergo blood testing using QFT
Note:If a patient has a documented x-ray within the previous 26weeks then it need not be repeated at screening.The x-ray must be reviewedand commented by a specialist
13.Has had an invasive malignancy within the past 5years
14.Has uncontrolled diabetes mellitus at Screening as defined by a
serum glucose>126 mg/dl.If the result of the glucose test is
>126mg/dL,then a confirmatory fasting test may be done and if >126 mg/dLthe patient must be excluded
15.Known HIV,hepatitis B or hepatitis C infection
16.Has undergone administration of any investigational drug within 30days of study initiation or intention to participate in any
investigational drug trial during the study
17.All biologic agents are excluded for 90days prior to Screening and throughout the study
18.Has undergone administration of rituximab or any Bcell depleting investigational drugs within 6months of Screening
19.Known or suspected history of alcohol or drug abuse within 2years prior to screening
20.Any other medical condition which may interfere with the conduct of this study in the opinion of the investigator
21.Has a history of hypersensitivity reaction to glucocorticoids and or dipyridamole
22.Has limited mental capacity or language skills such that simple
instructions cannot be followed or information regarding AEs cannot be provided |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the change in the DAS28-CRP score at the 12-week visit from the baseline DAS28-CRP pain score. The DAS28-CRP score measured at 4 and 8 weeks will be used by the adaptive modeling in order to learn efficiently about the 12-week effects of each of the treatment arms. A difference between arms of a 0.25 effect (mean change divided by the standard deviation) is considered meaningful for futility analyses. A difference less than this is considered unimportant.
We label the change from baseline in the DAS28-CRP score for subject i at weeks 4, 8, and 12 weeks as Yi4, Yi8, and Yi12, respectively. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Argentina |
| Brazil |
| Bulgaria |
| Chile |
| Hungary |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Serbia |
| Ukraine |
| 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
|
| Following the last patient-last dose, the completion of the 18 week follow-up of this last patient represents the end of 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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