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 |
chronic inflammatory disorder that affects many tissues and organs |
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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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
- To investigate the clinically relevant improvement in anti-inflammatory/analgesic activity after multiple doses of AK106-001616 compared with naproxen in patients with RA on
background oral MTX.
- To compare the safety of AK106-001616 to that of naproxen in patients with RA on background oral MTX. |
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E.2.2 | Secondary objectives of the trial |
- To compare the safety and efficacy of multiple, oral doses of AK106-001616 with those of naproxen in patients with RA on background oral MTX using pharmacodynamic (PD) urinary biomarkers.
- To compare the effect of AK106-001616 on the gastrointestinal (GI) tract to that of naproxen in a subpopulation of the RA patients on background oral MTX (based on optional Video Capsule Endoscopy [VCE] assessment). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has been diagnosed with adult-onset RA (as defined by the 1987 American College of Rheumatology [ACR] classification criteria) for at least 3 months.
2. Has a Functional Capacity Classification of I-III (as described in Appendix E of the protocol).
3. Has been stable on oral MTX therapy (5 to 25 mg administered as a single weekly dose) for at least 12 weeks.
4. Has RA activity at screening and at baseline (Day 1, pre-morning dose), defined as a 28-joint disease activity score (DAS28) of ≥3.2 and an increase in DAS28 score from screening to baseline that is >0 and ≤1.2 (baseline minus screening).
5. Between 18 and 65 years of age inclusive.
6. Is able to give voluntary written informed consent to participate in this trial.
7. If female and of childbearing potential, the patient must confirm she is using adequate contraception since last her menses, and have a negative result on the urine pregnancy test taken before the administration of the study drug. She must be willing to consent to the continued use of adequate contraception during the study and for 3 months after the study conclusion. Adequate contraception is defined as the use of 2 acceptable methods of birth control (ie, a hormonal contraceptive, intra uterine device, diaphragm with spermicide, and condom with spermicide). A condom alone is not considered an acceptable method of birth control.
8. If male with a sexual partner who is a woman of childbearing potential, the patient must confirm that he and his sexual partner agree to use 2 acceptable methods of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, and condom with spermicide) during the study and for 3 months after the study conclusion. |
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E.4 | Principal exclusion criteria |
(To meet 5000 character limit, only most important listed in full)
1. Has been diagnosed with a secondary, non-inflammatory type of arthritis (eg, osteoarthritis or fibromyalgia) that might interfere with the evaluation of the effect of study medication on RA symptoms.
2. Is pregnant or is breastfeeding.
3. Has taken any NSAID (including aspirin) within 5 times the half-life of the NSAID or a minimum of 2 days before the start of the baseline visit (defined as Day -1 for VCE assessment subgroup and defined as Day 1 for all other patients) or any analgesic within 24 hours before the baseline visit. Patients taking ≤150 mg aspirin per day for non-arthritis reasons for at least 30 days before the first dose of study medication will be permitted to enter the study and will be allowed to continue their aspirin regimen for the duration of the study.
4. Has taken any anti-ulcer drugs (ie, H2 blockers, proton pump inhibitors, etc) during the NSAID washout period.
5. Has been treated with:
- Anti-tumour necrosis factor (TNF) drugs or other biologicals (except rituximab), eg, anakinra, abatacept, in the past 3 months.
- Rituximab in the past 6 months.
6. Has begun taking DMARDs or immunosuppressants other than biologicals (eg, gold salts [including oral gold], sulfasalazine, MTX, azathioprine, antimalarials, penicillamine, combination therapies used in RA treatment, leflunomide) and other physical/surgical treatments for RA or has changed the dosing regimen of any of these medications within 12 weeks before receiving the first dose of study medication.
7. Has reduced MTX dose within 6 months before the first dose of study medication because of any side effect related to MTX administration.
8. Has begun taking oral corticosteroids or changed the dose regimen of oral corticosteroids within 4 weeks before receiving the first dose of study medication (doses of up to 10 mg prednisone or equivalent per day are allowed), or has received intramuscular, intra-articular or soft-tissue injections of corticosteroids within 8 weeks before receiving the first dose of study medication.
9. Has received any antineoplastic (other than MTX ≤25 mg/week or azathioprine as therapy for RA) during the 8 weeks preceding the first dose of study medication.
10. Has an active malignancy of any type or a history of malignancy (with the exception of patients who have been in remission for at least 5 years and patients who have a history of treated basal cell carcinoma or carcinoma in situ of the cervix).
11. (a) Has a history of 2 or more types of active peptic ulceration as below:
- GI bleeding
- Recurrent gastric ulcers
- Duodenal ulcers OR
(b) Has an oesophageal, gastric or duodenal ulcer within 30 days before the first dose of study medication; OR
(c) Has active GI disease that precludes NSAID therapy.
12. Has clinically significant chronic/acute hepatic or renal disorder or a significant coagulation defect.
13. Has 1 or more of the following:
- An abnormal screening laboratory test value that is considered by the investigator to be clinically significant
- A value that is >2 times the upper limit of normal (ULN) for AST or ALT at screening
- A value for serum creatinine >1.5 times the ULN at screening
- An absolute neutrophil count (ANC) <1800/mm3 (or WBC <3.5 x 109/L), haemoglobin <10 g/dL, or platelets <100 x 109/L at screening
14. Has a known hypersensitivity to paracetamol and/or NSAIDs.
15. Is taking a drug that is known to have an interaction with MTX (see protocol Appendix G)
20. Women of childbearing potential who have a positive urine pregnancy test before administration of study drug.
23. Has a positive screening for H. pylori that is not followed by H. pylori eradication treatment. If deemed appropriate in the opinion of the investigator, patients who test positive for H. pylori may receive an appropriate course of treatment as part of the routine clinical management of the patient. Such patients may be considered eligible for the study following conclusion of the treatment course, without need for further baseline re-screening for H. pylori (assuming that all other eligibility criteria are met). Selected laboratory parameters must be repeated following H. pylori eradication treatment if the screening window is to be extended beyond 21 days as a result of this eradication
treatment.
Other criteria: received another IMP within 90 days before first dose; previously received AK106-001616 or has previously been considered a screen failure in this study; currently uncontrolled medical disorder or other condition which in the opinion of the investigator makes the patient unsuitable; history of aspirin-induced asthma; pregnant women; positive urine screen for drugs of abuse; positive for hepatitis B or C; unable to communicate well with investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy endpoints:
- Patient global assessment of arthritis (VAS)
- Patient assessment of arthritis pain (VAS)
- Physician global assessment of arthritis (VAS)
- Number of tender/painful joints (68 joint count)
- Number of swollen joints (66 joint count)
- ACR20 responder index
- ACR50 responder index
- DAS28 score
- European League Against Rheumatism (EULAR) response criteria
- HAQ functional disability index
- Acute phase reactant (C-reactive protein)
- Erythrocyte sedimentation rate (ESR)
- Incidence of withdrawal due to lack of arthrtis efficacy
Safety endpoints:
- Adverse events
- Vital signs
- Clinical laboratory tests (clinical chemistry, haematology, serology, urinalysis)
- 12-lead Electrocardiogram (ECG)
- Physical exam
- Video capsule endoscopy (optional subpopulation)
Pharmacokinetic (PK) endpoints:
- AK106-001616 plasma concentration-time profiles will be evaluated in population PK analyses.
Pharmacodynamic (PD) endpoints:
- Urine efficacy PD biomarkers: LTE4/urine creatinine, PGE-M/urine creatinine
- Urine safety PD biomarkers: 2,3-dinor 6-keto PGF1α/urine creatinine, 6-keto PGF1α/urine creatinine, 11-dehydro TXB2/urine creatinine, 11-dehydro TXB2/urine 2,3-dinor 6-keto PGF1α ratio
- Serum PD biomarkers: matrix metalloproteinase 3 (MMP3), crosslinked N-telopeptide of type 1 collagen (NTX), interleukin-6 (IL-6), interleukin-10 (IL-10), TNF-alpha (TNFα) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timpoints of evaluation for patients who are not in VCE sub-group:
Patient global assessment of arthritis, Patient assessment of arthritis pain, Physician global assessment of arthritis, clinical laboratory tests, ECG and vital signs - Screening, Day 1 to Follow-Up.
Number of tender/painful joints, Number of swollen joints, HAQ functional disability index and ESR – Screening, Day 1 to Follow-Up.
DAS28 score – Screening and Day 1.
Adverse events and urine sample for PD – Day 1 to Follow-Up.
Physical exam - Screening
AK106-001616 plasma concentration-time profiles and blood sample for PK – Day 1, Day 14 and Day 28
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
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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
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End of trial is last visit of last subject |
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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 | 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 |