| 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 |
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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 | 13.1 |
| 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 |
| The primary objectives of this study are to evaluate the safety, tolerability and efficacy of multiple doses of CAM-3001 administered subcutaneously in subjects with at least moderately active RA. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
1) To evaluate clinical outcomes in RA
2) To explore CAM-3001 dose and the relationship with safety and efficacy
3) To evaluate the pharmacokinetics (PK) and immunogenicity of CAM-3001 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria:
1) Male or female
2) Age 18 through 80 years at the time of screening
3) Signed and dated informed consent, prior to receipt of any study medication or any study related procedures
4) A diagnosis of adult onset RA of at least 3 months duration as defined by the 1987 ACR classification criteria (Arnett et al, 1988)
5) Treatment with methotrexate (7.5 to 25 mg/week) for at least 12 weeks and at stable and tolerated doses for at least 4 weeks prior to Screening.
6) Positive anti-cyclic citrullinated peptide (CCP) IgG antibodies (> 5 IU/mL) and/ or rheumatoid factor (> 14 IU/mL) at screening
7) Subjects must receive ≥ 5 mg/week folic acid as a single or divided dose during the study
8) At least moderately active disease as defined by DAS28 ≥ 3.2 at screening and baseline (Smolen et al, 2003)
9)a) Females of childbearing potential; unless surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy), has a sterile male partner, is premenarchal or at least 2 years postmenopausal, or practices abstinence; must use 2 effective methods of avoiding pregnancy (including oral, transdermal, or implanted hormonal contraceptives, intrauterine device, female condom with spermicide, diaphragm with spermicide, cervical cap with spermicide, or use of a condom with spermicide by the sexual partner) for 21 days prior to randomisation and at baseline, and must agree to continue using such precautions until the end of the 12 weeks safety follow-up; cessation of birth control after this point should be discussed with a responsible physician. A negative pregnancy test is required both at screening and prior to dosing.
b) Males, unless surgically sterile, must use 2 effective methods of birth control with a female partner and must agree to continue using such contraceptive precautions from screening through the end of the 12 weeks safety follow-up
10) No evidence of medically significant respiratory disease. A local pulmonologist will review subjects’ respiratory system including, chest x-ray, pulmonary function, and diffusing capacity for carbon monoxide (DLCO), which are performed at screening. Subjects must have:
DLCO ≥ 80% predicted value
Forced expiration volume in first second (FEV1) by spirometry ≥ 80% predicted value
No pneumonitis and clinically significant obstructive or restrictive lung disease
11) Willing and able to comply with the protocol and complete the study period
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| E.4 | Principal exclusion criteria |
Any of the following would exclude the subject from participation in the study:
1) A rheumatic autoimmune disease other than RA, or significant systemic extra-articular involvement secondary to RA. Subjects with secondary Sjögren’s syndrome or secondary limited cutaneous vasculitis with RA are eligible
2) A history of, or current, inflammatory joint disease other than RA or other systemic autoimmune disorder
3) Functional class IV defined by the 1992 ACR Classification of Functional Status in RA
4) Treatment with any investigational drug therapy within 28 days or 5 half-lives of the drug, whichever is longer, prior to screening
5) Previous treatment with > 1 biologic therapy for RA that was discontinued for lack of efficacy
6) Any cell depleting therapies within 12 months prior to screening; or previous treatment with non-depleting biologic therapies within 30 days or 5 half-lives of the biologic agent, whichever is longer, prior to screening
7) Previous administration of CAM-3001
8) History of known allergy or reaction to any component of the CAM-3001/investigational product formulation
9) Treatment with disease modifying anti-rheumatic drugs, other than background methotrexate within 28 days of screening.
10) Treatment with alkylating agents 12 weeks prior to screening
11) If receiving treatment with non steroidal anti-inflammatory drugs these must be on a stable dose for ≥ 28 days prior to baseline and remain stable for the duration of the treatment phase of the study.
12) Intramuscular, IV or intra-articular corticosteroids within 28 days of screening
13) Treatment with > 10 mg/day dose prednisone (or equivalent) within 28 days of screening. Concomitant treatment with oral steroids ≤ 10 mg/day prednisone or equivalent is permitted providing that the dose is stable for ≥ 28 days prior to screening and remains stable for the duration of the treatment phase of the study.
14) Female subjects who are pregnant, intend to become pregnant, or are breast-feeding
15) Subjects who in the opinion of the investigator have evidence of active tuberculosis (TB), either treated or untreated, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment.
16) Current symptoms and signs of clinically significant chronic or recurrent infection and any significant chronic or recurrent infection, or any episode of infection requiring hospitalisation 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 at a high risk of infection
18) History of hereditary or acquired immune deficiency disorder
19) Receipt of live vaccine within the 28 days before screening or during the study
20) Any history of cancer except basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured
21) Any surgical procedure, including bone or joint surgery/synovectomy within 12 weeks prior to screening or any planned surgery within 3 months after randomisation
22) Any neurological, psychiatric, vascular, or systemic disorder could also affect the evaluation of efficacy assessments; in particular, joint pain and swelling
23) Significant respiratory or pulmonary disease including symptomatic lung fibrosis, pneumonitis, uncontrolled asthma, dyspnoea, malignancy and history of chronic respiratory tract infections
24) Congestive heart failure NYHA classification III or IV
25) History of methotrexate or any drug induced lung fibrosis or pneumonitis
26) History of deep space/tissue infection within 12 months prior to screening.
27) Evidence of any disease or history of any disease, any finding upon physical examination, or any clinically significant laboratory or radiographic abnormality that, in the opinion of the investigator, designated health care provider, or medical monitor, may compromise the safety of the subject in the study or confound the analysis of the data
28) At Screening blood tests; any of the following:
Aspartate transaminase (AST) > 2.5 x upper limit of the normal range (ULN)
Alanine transaminase (ALT) > 2.5 x ULN
Haemoglobin (Hb) < 8.0 mg/dL
Neutrophils < 1,500/mm3 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
The effect of CAM-3001 on the response rate in terms of improvement in DAS28 c-reactive protein (CRP) score on the day of last dose of study drug (Study Day 85) will be evaluated. According to the European League Against Rheumatism (EULAR) response criteria an improvement from baseline in DAS28(CRP) of more than 1.2 would be considered a good response in subjects experiencing low disease activity (baseline DAS28 < 3.2) and a moderate response in subjects experiencing medium to high disease activity (baseline DAS28(CRP) ≥ 3.2). A responder will be defined as a subject experiencing a decrease of more than 1.2 from their baseline DAS28(CRP) score, on the day of last dose of study drug (Study Day 85 per protocol). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| The secondary endpoints of this study include disease activity, the onset of response, duration of response after withdrawal of treatment, need for additional medications during the study and the PK and immunogenicity of multiple SC doses of CAM-3001. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The onset of response, duration of response after withdrawal of study treatment and need for additional medications during the study (Yes/No) will be summarised and tabulated together with descriptive statistics and listed by treatment arms. The time-to-events endpoints; the onset of response, duration of response after withdrawal of treatment will be analysed using non-parametric log-rank method and also Cox proportional hazard models (modelling baseline covariates as appropriate). |
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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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| Bulgaria |
| Czech Republic |
| Estonia |
| Hungary |
| Japan |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
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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
|
| Study completion is defined as the date of the last protocol-specified visit/assessment for the last subject in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 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 |
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