Study Objectives
The principal objective of the study is to determine whether rheumatoid arthritis (RA) can be prevented or delayed if targeted immunotherapy is administered to subjects in whom autoantibody screening indicates a high risk of developing disease. Specifically, this study will test the hypothesis that the onset of arthritis in an “at risk" group can be prevented or delayed by weekly injections of abatacept for a period of 52 weeks.
The specific aims of study are to:
1. Evaluate the feasibility, efficacy and acceptability of abatacept therapy in subjects at high risk of developing RA, and
2. Characterise immune and inflammatory responses associated with ACPA before, during and after therapy with abatacept.
Trial Design
The APIPPRA trial is a randomised, placebo controlled, double-blind multicentre trial undertaken at 31 specialist rheumatology clinics across the UK and the Netherlands. The trial was designed to ascertain the effectiveness of abatacept in ACPA+RF+ or ACPAhighRF- subjects with arthralgia who are deemed to be at high risk of developing rheumatoid arthritis (RA). Eligible subjects will be randomly allocated to receive weekly injections of either abatacept or placebo treatment over a 52 week period. This provides the best chance of establishing whether differences observed between the two groups are due to the treatment. The study design is shown in Figure 1.
Study population
The APIPPRA study will recruit study subjects who are at high risk of developing RA who show no clinical evidence of joint swelling. Participants may be recruited using a range of ethically approved methods, including during rheumatology out-patient clinics, following referral to recruiting centres from other rheumatology out-patient clinics, referrals from GP practices through the routine referral pathway or patient identification centre (PIC) pathway, or through existing research databases and registries. Subjects may be identified by pre-screening of laboratory results for RF and ACPA.
Eligibility criteria
Inclusion Criteria
1. Male or female subjects, aged ≥ 18 years.
2. Arthralgia, defined as non-traumatic joint pain localised to synovial joints including, but not necessarily confined to, hands, wrists or feet, and in the opinion of the supervising rheumatologist considered to be inflammatory in nature.
3. Positive for serum rheumatoid factor (RF) and antibodies to citrullinated protein antigens (ACPA) as defined by local clinical laboratory testing. Subjects who are RF negative, but who carry high levels of serum ACPA (defined as being ≥ 3 x upper limit of normal [ULN] for the assay) may be included.
4. Able and willing to give written informed consent and comply with the requirements of the study protocol.
Exclusion Criteria
Target disease exceptions
1. Previous diagnosis of RA or other form of inflammatory arthritis including, but not limited to Systemic Lupus Erythematosus (SLE), psoriatic arthritis, ankylosing spondylitis, gout or pyrophosphate arthropathy, and including current treatment with DMARDs or biological therapy.
2. Arthralgia that, in the opinion of the supervising physician, is poorly localised e.g. pelvic or shoulder girdle pain, that is confined to the axial skeleton or entheses, or pain which the physician considers to be due to osteoarthritis or fibromyalgia or related to other autoimmune conditions such as type I diabetes, coeliac or autoimmune thyroid disease.
3. Clinically apparent inflammatory arthritis, as assessed by a rheumatologist, characterised by soft tissue swelling of one or more synovial joints. Subclinical synovitis, as detected by imaging modalities such as ultrasonography or MRI, is NOT an exclusion criterion.
4. A history of oral or parenteral use of corticosteroids within the last 12 weeks used to treat the current episode of musculoskeletal symptoms.
5. Co-morbidities requiring chronic treatment with immunosuppressive or immune modulating therapy.
6. Subjects who have at any time received treatment with any investigational drug within 28 days of the first dose of study drug.
7. A history of acute allergic reactions to biological therapy or immunoglobulins
Medical history and concurrent diseases
1. Subjects who are incapable of completing study-related assessments or give informed consent.
2. Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, whether or not related to RA and which, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
3. Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ.
4. Subjects with tuberculosis (TB), including those at high risk of TB, chronic viral infections, recent serious bacterial infections, subjects receiving live vaccinations within 3 months of the anticipated first dose of study medication, or those with chronic illnesses that would, in the opinion of the investigator, put the participant at risk.
5. Subjects who currently abuse drugs or alcohol.
6. Subjects who are pregnant or breastfeeding, or women of child bearing potential not willing to use adequate contraception during the period of IMP dosing and for up to 14 weeks after the last dose of study drug.
7. Male subjects not willing to use adequate contraception during the period of IMP dosing and for up to 14 weeks after the last dose of study drug.
Physical and laboratory tests at screening
Subjects must not test positive for:
1. Latent tuberculous infection according to the interferon gamma release assay. Subjects who are positive and who have been treated for ≥ 4 weeks may be selected.
2. Antibodies to hepatitis B surface antigen.
3. Hepatitis C antibody if the presence of hepatitis C virus was also shown with polymerase chain reaction or recombinant immunoblot assay.
4. HIV.
Subjects with any of the following laboratory values or other test results that in the opinion of the Principal Investigator, might place a subject at unacceptable risk for participation in the study:
1. Haemoglobin < 85 g/L
2. WBC <3 x 109/L
3. Platelets < 100 x 109/L
4. Serum creatinine > 2 times the ULN
5. Serum ALT or AST > 2 times the ULN
Trial intervention
Investigational medicinal product/placebo schedule and administration
Abatacept will be administered by subcutaneous injection at a dose of 125 mg/injection (125 mg/mL). Placebo is supplied as identically labelled injections containing a sterile saline solution for subcutaneous administration. Investigational medicinal product (IMP) is supplied as kits of four pre-filled syringes with coded label.
Treatment period (weeks 0-52)
Following randomisation, participants will start their dosing regimen at the baseline visit. Abatacept (or placebo) will be injected weekly at the recommended dosage of 125 mg/ml for 52 weeks. Participants are trained to self-administer study drug subcutaneously (for the first injection) using the single-dose prefilled syringe according to local practices for the administration of biological therapy as part of standard care. Participants will be given 3 months’ worth of study medication at baseline and at each subsequent 3 monthly scheduled visits during the first 12 months. Participants will also be given information about the study drug, such as the Arthritis Research UK (now Versus Arthritis) Drug Information leaflet, according to local practise. Subjects will also be given a study medication diary card to record their weekly injections.
In the event of missed doses, participants should not take their medication unless it is within ± 3 days of the scheduled medication dosing date. In addition to the 3 monthly visits, there will be brief telephone consultations, once a month, to check that study subjects are administering their weekly injections, and to ask if there have been any changes in their symptoms.
Follow up period (weeks 53-104):
Once participants have completed the 52-week course of IMP/placebo, they will be seen in the outpatient clinic every 3 months for similar assessments (see Table 1; Schedule of blood and urine sampling) to those in year 1, to monitor the impact of the treatment phase. This follow up period is especially important because if at any time participants develop new joint pains or swelling they will be assessed promptly and treated appropriately, in a similar way that clinical staff would assess any new patient presenting with similar symptoms.
Concomitant Medication
For the duration of the trial the investigator or another healthcare professional (for example GP) may prescribe simple analgesics or non-steroidal anti-inflammatory drugs considered necessary for the treatment of the participant’s joint symptoms. Treatments for concurrent non-rheumatic disorders will be given as needed provided that they are not expected to interfere with the evaluation of the study medication. The following drugs, however, are not permitted before the onset of clinically apparent synovitis (primary endpoint):
· Oral or parenteral glucocorticoids; short courses (< 2 weeks) of oral or parenteral steroids will be permitted for the treatment of significant, non-rheumatic, concurrent illnesses, including but not confined to asthma and chronic obstructive pulmonary disease.
· Disease modifying anti-rheumatic drugs.
· Any other biological agent for the treatment of RA.
· Any other medicinal product that may, in the supervising physician’s opinion, influence underlying disease activity through effects on immune and/or inflammatory responses (with the exception of NSAIDs).
Treatment of study subjects reaching primary endpoint
For those study subjects achieving the primary endpoint – the development of clinically apparent synovitis or RA – the use of corticosteroids and disease modifying anti-rheumatic drugs will be permitted, the choice of therapy being left to the discretion of the supervising physician. All subjects remain in the study and complete follow up assessments according to the schedule of visits (see Table 1, Trial Flowchart), including full documentation of treatment for their inflammatory arthritis.
Study assessments
Following screening, all participants will undergo baseline study visits and then 3 monthly follow up visits for the duration of the trial. Clinical assessors will be blinded to joint assessments by ultrasonography.
Participants will follow the visit schedule summarised in Table 1 unless participants consider that they are experiencing a worsening of symptoms, or have developed swelling of joints, in which case participants will be seen within two weeks. In addition to attending the 3 monthly assessments, they will be telephoned by their Research Nurse or designated staff involved in the study every month (during the treatment period) to check that study subjects are adhering to their study medication and managing their symptoms. Details of assessments and flexibility at scheduled visits are shown in Table 1.
The baseline assessment should be performed no later than four weeks after the screening assessment. For all subsequent assessments, if participants cannot attend on the due date, a two-week window either side of the assessment due date will be permitted
Unscheduled visit assessments
These assessments will be undertaken for subjects experiencing worsening of symptoms or swelling of joints between scheduled visits. Study subjects will be seen promptly, and usually within 2 weeks of new signs and symptoms developing.
1. Physical examination
2. Disease Activity (includes Extended joint counts 68/66, DAS28, SDAI, CDAI, Pain VAS and Physician and patient global assessments (VAS))
3. ACR/EULAR remission, as defined (18)
4. Acute Phase reactants - ESR and C-reactive protein
5. Patient Questionnaires as listed above at baseline visit.
6. Confirmation of clinically apparent synovitis by ultrasonography
7. Blood for biomarkers (this will replace the subsequent scheduled blood draw when the date of the unscheduled visit precedes the next scheduled visit by ≤ 4 weeks)
8. Urine for biomarkers (this will replace the subsequent scheduled urine collection when the date of the unscheduled visit precedes the next scheduled visit by ≤ 4 weeks)
Ultrasonography
Participants will also undergo imaging by ultrasonography. This part of the APIPPRA study will be undertaken in those recruiting centres that provide this service as part of routine clinical care, and/or where there are personnel trained in musculoskeletal ultrasound using imaging equipment approved by the APIPPRA study investigators (e.g. probes with a frequency of at least 12mHz and acceptable power Doppler sensitivity).
Scans will be performed at baseline, 6, 12, 18 and 24 months (and at any point between where the supervising physician believes that the study subject has achieved the primary endpoint). At each scanning visit, designated sonographers will scan a core set of joints including, but not confined to, dorsal views of the wrists, metacarpophalangeal (MCP1-3), proximal interphalangeal (PIP2,3), and metatarsophalangeal (MTP2-5) joints. Grading of grayscale and power Doppler measurements will be documented by applying semi-quantitative scales dictated by atlases provided to each participating centre. The scanning process will be scheduled before treatment is initiated for the baseline scan, and within 2 weeks either side of scheduled 6, 12, 18 and 24 month visits, if scans cannot be accommodated at the same time as scheduled visits.
In addition to the above assessments, ultrasound evaluation will be performed to confirm whether the study subject has met the primary outcome, and will include the core set of joints, as above, as well as imaging of any additional symptomatic joints. Ultrasound assessments and scores will be added to the eCRF upon completion of the imaging study and scores will be blinded to the supervising PI or clinical assessor. Anonymised copies of images will be either stored on CDs and securely mailed or sent electronically to a secure email address in a central unit so that scores can be reviewed to ensure consistency of assessments across centres.
X-ray Imaging
All X-ray images will be uploaded onto a dedicated, password protected web-based system and will be scored centrally.
Routine Clinical Laboratory Tests
Study subjects will undergo routine blood monitoring to screen for biological therapy related toxicity at all assessments, or according to local practice if more frequent.
Routine blood monitoring beyond the 12 month study visit will be taken only if clinically indicated, and left to the discretion of the supervising physician
Exploratory Laboratory Tests
These assays will be undertaken by the study investigators or designated collaborators either within or outside of the UK, as agreed and designated by the APIPPRA study investigators. Samples of blood and urine will be transported from recruiting sites across the UK and the Netherlands to pre-designated laboratories based in academic centres for processing and storage. Subsequently, all samples will be shipped from processing hubs in batches to the UK Biocentre for long term storage prior to distribution to the relevant research laboratory for subsequent biomarker analysis as outlined below.
The schedule of blood and urine sampling is summarised in Table 2.
Study endpoints
Primary endpoint
The primary endpoint of this study is the time to development of clinical synovitis or RA defined by one of the following methods, whichever is met first:
1. The time to development of clinically apparent synovitis in ≥ 3 joints, as determined by two independent assessors with experience in clinical assessment of RA.
2. The time to development of RA according to the ACR/EULAR 2010 classification criteria (19), where joint involvement is defined as joint swelling.
In either case joint swelling will be confirmed by ultrasonography (Figure 2). If the primary endpoint is not confirmed, study participants continue IMP.
Secondary endpoints
The secondary endpoints of this study are:
1. The development of RA according to the ACR/EULAR 2010 criteria where joint involvement based on ultrasound assessments will be included.
2. Assessments of disease activity and progression over time, using DAS28 (tender and swollen joint counts, patient global visual analogue score (VAS), ESR), Extended Joint Count 68/66, Simple Disease Activity Score (SDAI) and Clinical Disease Activity Score (CDAI), Pain VAS, Lifestyle Factors Questionnaire, Health Assessment Questionnaire (HAQ), Modified Illness Perception Questionnaire (Modified IPQ), Euro-Quality of Life Questionnaire (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Work Instability Scale (RA-WIS), Functional Assessment of Chronic Illness Therapy- Fatigue Questionnaire (FACIT-F) and Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire.
3. The proportion of participants requiring DMARD therapy, and the time to commencing DMARD therapy, including oral or parenteral corticosteroids.
4. Progression of radiographic changes in X-rays of the hands and feet scored by van der Heijde Sharpe Modified Scores or using the Larsen score.
5. Changes in scores of synovitis and vascularity defined by ultrasonography and power Doppler over time.
6. Adverse events.
Exploratory endpoints
1. Changes in serum ACPA levels over time.
2. ACPA isotype and antigenic fine specificity over time.
3. Signatures of immune and inflammatory responses as defined through analysis of serum, peripheral blood cell subsets, peripheral blood RNA expression profiling and urine.
Statistical considerations
Randomisation procedure, blinding and data management
If the participant is willing to participate in the trial, informed consent will be obtained at the start of the screening visit. Screening assessment data will be entered by sites onto a web-based InferMed MACRO Electronic Data Capture (EDC) system hosted on a dedicated secure web site by King’s College London, using only the participant’s initials and date of birth as identifiers. The EDC system will automatically assign a unique participant identification number (PIN) to each participant as they are registered onto the EDC system. Participants who consent to screening but who are subsequently found to be ineligible will also be recorded in the EDC system, for CONSORT reporting purposes. These procedures will operate in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines for good clinical practice (GCP), meeting the requirements of the Medicines and Healthcare products Regulatory Agency (MHRA).
Once participants are confirmed eligible, authorised study site staff will access the web-based randomisation system and enter the PIN, initials and date of birth of the participant along with details of any characteristics to be used in the randomisation algorithm. Staff at individual centres and the sponsor will be unaware of the allocation sequence.
Participants will be randomised to IMP (abatacept) and placebo groups using the method of stratified randomisation with randomly permuted blocks within strata defined by gender, country (UK, Netherlands) and smoking status (never, previous and current). Once randomised, the system will automatically recognise what active and placebo kit numbers are available in the site pharmacy and will select 4 blinded treatment kit numbers from the appropriate trial arm and this will be allocated to the participant. At each follow up visit, site staff will again access the randomisation system and allocate new treatment kits for the participant. All participants and staff involved in the conduct of the study will be blind to treatment allocation throughout the trial.
Assessment of Safety
All subjects who receive study drugs will be evaluated for safety. Safety outcomes include adverse events, clinically significant changes in vital signs, laboratory test abnormalities, and clinical tolerability of the drug. The investigator will determine the severity of each adverse event as mild, moderate, severe, or very severe. Laboratory findings that the investigator feels are clinically relevant will be recorded as adverse events. In addition, the investigator will determine the relationship of the adverse event to the administration of the study drug. Any occurrence of a serious adverse event (SAE) from time of consent forward, up to and including follow-up visits will be reported.
Sample Size
Using time to development of arthritis as the primary outcome, or development of RA within 24 months of follow-up, according to 2010 ACR/EULAR criteria, a total of 52 study subjects need to present with this endpoint from 206 randomised, based on the following information. It is anticipated conservatively that 40% of participants on placebo will develop arthritis. A sample size of 172 subjects would be needed to provide 80% power, to detect a 50% relative reduction to 20% in the abatacept arm (a hazard ratio of 0.437), based on a two-sided log rank test at the 5% level of significance, without loss to follow-up of any of the required 52 events. Therefore 206 subjects (103 per arm) will be randomised to allow for loss of events due to dropout, applying a conservative 20% inflation for dropout.
Similar effect sizes are detectable for binary outcomes and for other time-to-event and proportion outcomes such as the development of RA according to ACR/EULAR 2010 criteria alone. For continuous secondary outcomes, such as disease activity score measures, a medium effect size difference in means (of size 0.5 of a Standard Deviation) between the arms, based on the unpaired t-test at the 5% significance level can be detected with 85% to 90% power if 146 to 172 subjects are followed up. In view of the number of required secondary outcomes, with 172 participants followed up, there is also 80% power to detect medium sized effects in secondary outcomes (0.52 of a SD) using a secondly applied significance level of 1%. Analyses incorporating baseline adjustment and/or repeated measures data will provide increased precision.
Withdrawal of Subjects
Participants will be free to withdraw at any time. Participants who do withdraw from IMP will be invited to return for milestone assessments (at months 3, 6, 9 and 12, or at months 15, 18, 21 and 24, depending on the phase of the study) so that data may be collected and changes in their disease can be assessed; it will be made clear to them that this is entirely at their own discretion.
Subjects will discontinue investigational product (and non-investigational product at the discretion of the investigator) for any of the following reasons:
1. Withdrawal of informed consent (subject’s decision to withdraw for any reason).
2. Any clinical adverse event, laboratory abnormality, or intercurrent illness which, in the opinion of the Principal Investigator, indicates that continued participation in the study is not in the best interest of the subject.
3. In the Principal Investigator’s opinion, the need to administer concomitant medication not permitted by the trial protocol.
4. Pregnancy.
All subjects who discontinue should comply with protocol-specified follow-up procedures. The only exception to this requirement is when a subject withdraws consent for all study procedures or loses the ability to consent freely. If a subject withdraws before completing the study, the reason for withdrawal will be documented appropriately.
Statistical analysis
The primary analysis approach will be an intention to treat strategy including sensitivity analysis for missing data (20), sensitivity analysis for low compliance (21), and sensitivity analysis for use of forbidden rescue medication or potential informative dropout (described in the detailed statistical analysis plan).
For each time to event outcome, including the primary outcome, Kaplan Meier survival curves will be estimated. A Cox stratified proportional hazards regression model, accounting for the randomisation stratifiers in the form of nominal categorical variables, will be used to compare randomised arms and obtain an estimated hazard ratio for the treatment effect with 95% confidence interval. Participant follow-up is on a three-monthly basis, with additional monthly phone calls when participants will be able to additionally report on their progress. Days will be the unit of time within the model in order to fully capture the inevitable variation in the time from baseline to monthly contacts and to ascertained outcome events. Each participant who drops out will be included in the analysis and will be assumed not to have the event and be censored at the point of dropout. For the primary outcome, sensitivity analysis will be carried out.
For each binary outcome, a stratified difference in proportions using the Cochran-Mantel-Haenszel method will be used to compare arms accounting for the randomisation stratifiers in their nominal categorical form. For each continuous outcome, including DAS28, differences in the mean of the outcome between arms will be estimated using a linear mixed effects regression model of the repeated measures of the outcome over time, with terms for the polynomial trend through the visit time points, and with advantageous adjustment for the correlated baseline of the outcome, if this is available, and for the randomisation stratifiers. The missing indicator method (21) will be used to enable those participants having any outcome data, but with missing baseline data, to contribute to the estimate.
All tests will be two-tailed and primarily assessed at the 5% level of significance. Tests will be carefully interpreted against the hierarchy of the study objectives, and by using 95% confidence intervals to exclude overly strong negative or positive clinical conclusions. The trial is powered to allow a secondary 1% level of significance to be applied to allow safer interpretation of multiple secondary outcomes. Descriptive statistics will be reported for measures of acceptability, feasibility and safety. Percentage measures will be reported with exact 95% confidence intervals. There is no plan to have stopping rules. It is anticipated that the Data Monitoring Committee will request interim data on safety and will advise on further data required for monitoring, and on trial statistician blinding status. A detailed statistical analysis plan will be developed from the study protocol prior to the availability of follow-up data for approval by the independent Trial Steering Committee (TSC). The primary analysis will follow the intention to treat (ITT) principle, that is, participants will be analysed in the groups to which they were randomised irrespective of treatment received, utilising all available follow up data from all randomised participants, with a per protocol analysis of compliers only, as defined in the statistical analysis plan. Alterations to the statistical analysis plan will require re-approval from TSC.
Trial oversight
An independent data monitoring committee (DMC), comprising a committee Chair, the APIPPRA study trial statisticians, one independent statistician, and at least two independent members with experience in RA trials, will be responsible for monitoring evidence of harm and for reviewing decisions relating to all aspects of safety reporting. They will meet prior to initiation of the study and at approximately 6 monthly intervals, or at more frequent intervals as deemed appropriate, for the duration of the study. The statistical analytical plan will be used to guide decision making.
The Trial Steering Committee (TSC) will include an independent Chair, the Chief Investigator and core study team, an independent statistician, at least two clinicians with experience in RA trials who are not otherwise involved in the study, and an experienced patient expert as patient representative. The TSC is main decision-making body and will be responsible for trial conduct and scientific direction and will ensure that the study objectives are achieved in a timely fashion and within budget.