| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 REUMAP study is a safety-biased, open-label proof of concept study that aims to explore a possible beneficial effect of alkaline phosphatase in active RA patients who show insufficient response to current therapy. We anticipate observing a reduction of pro-inflammatory cytokines (TNFα, IL6)and standard inflammatory measures (ESR and CRP) subsequent to subcutaneous administration of low doses of exogenous alkaline phosphatase. A panel of additional cytokines and inflammatory markers will be measured in an exploratory fashion as will serum AP.
Since SC administration is novel in humans, we will observe patients specifically for cutaneous reactions as a co-primary variable as well as general safety. It is for this reason that we have scheduled the administration as a safety-biased cohort design.
TNF inhibition is an effective therapy in RA. We will therefore observe patients’ clinical condition for a total of 3 months using standard clinical measures such the RA disease ac |
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| E.2.2 | Secondary objectives of the trial |
Secondary Outcome Measures. Day 1-8 Laboratory Phase.
will be adverse events, change in RA clinical status expressed as DAS and ACR scores, general well being and duration of clinical response measures observed daily during the injection days (1-3) and on days 4, 6 and 8 of the 8 day laboratory phase.
Secondary Outcome Measures. Days 9-84 (weeks 4-12): The Clinical Phase
1.Secondarily, the cytokine profiling will be correlated with the clinical response expressed as the DAS 28 and ACR response scores and longer-term clinical improvement over the subsequent 3 months (the Clinical Phase).
2.Clincial Phase Measurement of Primary and Sub Primary Outcome Measures.
Following the defined dosing regime (3 days) we expect that pro-inflammatory responses will recur in the 5 days post administration time period. However, to detect any unexpected prolonged alterations, we will collect serum to measure all primary and exploratory variables including AP at the time of monthly routine safe |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The total cohort of patients is small, only 10 patients. We will attempt to make the population as homogenous as possible.
1.12 Inclusion Criteria
1. Male or non-pregnant, non-lactating female patients of any race with an age >18 years. Woman of child-bearing potential must be on regular contraceptives throughout the trial. Pregnancy tests will be used at screening for women of child bearing years.
1A: RA according to the 1987 revised ARA criteria (Arnett 1987) with an active disease with DAS28>3.2 despite the prior or concurrent use of DMARDs.
2. Patients may be on no active therapy or may be on continuous DMARD therapy including Methotrexate, Sulphasalazine, Leflunomide, Hydroxychloroquine, Myocrisin alone or in combination, or on NSAID treatment, or on steroid (prednisolone not more than 10mg/day) provided that the regime has been stable for 30 days prior to screening. All prior medication should be maintained at steady dosing throughout the 8th day laboratory phase. Intra-articular or subcutaneous steroid are not allowed during the laboratory phase. Alterations may be made at the discretion of the investigator during the 3-month clinical follow-up period in accordance with standard of care. All such alterations will be recorded and reported. Joints receiving IA injections will be counted as positive for subsequent tender and swollen joint counts.
3. Patients must have a measurable acute phase response: CRP (> 10mg/dl)or ESR > 25. (to be measured on routine lab range CRP/ ESR/AP/ standard biochemistry)
4. Patients eligible for treatment with biological TNFα blockers and who are awaiting the administration of such treatment may enrol in the laboratory and safety protocols Data for Clinical Phase observations will be collected but will be handled as last observation carried forward for the final records prior to the administration of TNF blocking agent, should that occur within the 3-month Clinical Phase. The administration of TNFα blockers will not be delayed for the protocol.
5. Patients who have given written informed consent prior to participation in
the trial and who undertake to comply with the protocol.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
1. Patients who are unwilling or unable to be fully evaluated for follow-up.
2. Patients who have an active infection or who are suspected of having systemic infection and or patients that are treated with antibiotics.
3. Patients who have evidence of significant hepatic disease, including history of clinical signs or laboratory values of total bilirubin > 34.2 umol/L (> 2.0 mg/dL), ALT (>120) or AST (>135) corresponding to > 3X upper limit of normal.
4. Alkaline phosphatase levels must be less 145 IU/L (routine clinical method)and patients with too low observed acute phase rsponse (ESR/CRP) on screening bloods.
5. Patients who received investigational drugs in the 30 days prior to study drug administration, or are currently participating in a study during which
the administration of investigational drugs within one month is anticipated.
6. Patients who have renal insufficiency (history of creatinine >177umol/L or >2.0 mg/dL) or chronic renal failure requiring dialysis.
7. Patients with severe neurological deficits (see Appendix I).
8. Patients who have a recent history of drug substance or alcohol abuse.
9. Patients with a diagnosis of idiopathic thrombocytopenia.
10. Patients with a history of cancer who have received chemotherapy or radiation therapy within the past 3 months. Patients receiving only adjuvant hormonal therapy are not excluded. If the cancer has not resolved completely, the patient should not be enrolled without permission of Alloksys.
11. Patients receiving oral glucocorticoids >10mg /day or any IV, IM or Intra articular dosing within 30 days of commencing the protocol.
12. Patients who are vegetarians or veganists or those patients that may be expected not to be tolerant to bovine proteins.
13. Patients who are, in the opinion of the Investigator or the Sponsor, unsuitable for the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Outcome Measures. Days 1-8. The Laboratory phase.
This study is designed to test the following hypotheses: SC administration of 2 injections of 2000 IU bIAP daily (8 hours apart) for 3 days results in a measurable reduction of TNFα and IL-6 in blood, measured by Luminex cytokine profiling along with conventional measures of ESR and CRP. These are the primary outcome measures.
Sub Primary and Exploratory Laboratory Measures
Cytokines
Additionally, a number of potential cytokine targets will be measured in the same samples in an exploratory fashion including IL-1a, IL1b,IL-8, IL-10, IL-12, IL-15, IL-17, IL-18, sTNFr and RANKL.
Alkaline Phosphatase
In previous CABG studies (APPIRED 1 and APPIRED pilot 2) a late peak of endogenous AP production was seen 3-4 hours after after IV administration of exogenous AP. This endogenous AP response lasted for more than 36 hours. This has also been seen after SC admin in experiemntal piglets (see IB). Therefore, the response of endogenous AP levels to exogenous SC administration will also be explored.
Co-Primary Safety Outcomes and Safety Design
Since SC administration of bIAP is novel in humans, we will specifically record cutaneous reactions as a co-primary safety variable. Patients will be observed throughout day 1 of injection then at times of injection on days 2 and 3, then once daily on days 4, 6 and 8. Full safety monitoring and AE recording will be carried out. As an additional safety feature, patients will be treated in cohorts. The first patient will complete the laboratory phase and nreports made to the DMC before the second cohort of two patients are treated, these will complete the laboratory phase before further cohorts of three then a final four patients are treated.. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | 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) | 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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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| last patient, last visit week 12 |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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