Rheumatoid ArthritisPhase 4NCT01893996
Study of Adalimumab to Lower Cardiovascular Risk in RA Patients With Well Controlled Joint Disease
A Phase 4 study testing Adalimumab in people with Rheumatoid Arthritis and Cardiovascular Disease, run by Jonathan Graf at 1 site in United States.
Trial summary
Rheumatoid arthritis patients are at increased risk of cardiovascular disease because of systemic inflammation that can persist even in patients with well-controlled joint disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rheumatoid Arthritis, Cardiovascular Disease
- What is being tested?
- Adalimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 63 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2013to Jul 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subject must be able and willing to give written informed consent and comply with the requirements of the study protocol.
- Diagnosis of Rheumatoid Arthritis by ACR 1987 or ACR/EULAR 2010 criteria.
- Low RA disease activity as defined by DAS28 < 3.2
- No anti-TNF medication or other biologic agent (abatacept, rituximab, or tocilizumab) within the 12 months prior to enrollment.
- If taking methotrexate, then on a stable dose between 7.5 mg and 25 mg (PO or SQ) weekly for at least 3 months prior to randomization. If on a DMARD other than methotrexate, then that DMARD must be at a stable therapeutic dose for at least 3 months prior to randomization.
- If taking prednisone, then a stable dose of less than or equal to 10 mg/daily for at least 1 month prior to randomization
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- If NSAID taken on a regular, daily schedule, then patient must be on a stable dose for one week prior to FMD studies. PRN use is excluded within 1 week of FMD studies.
- Age > 18
- Subject must be able and willing to self-administer SQ injections or have available qualified person(s) or caregiver to administer SQ injections
- Negative serum pregnancy test (for women of child bearing age)
- Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment
- Adequate renal function as indicated by serum creatinine < 2.0.
- No use of phosphodiesterase type 5 inhibitors (PDE5) (i.e. sildenafil, tadalafil, and vardenafil) 1 week prior to the study and during the course of the study.
Who cannot join
- Use of an anti-TNF or other biologic medication (Including but not limited to abatacept, rituximab, or tocilizumab) within the previous 12 months.
- Prior history of MI, CVA, CABG, PTCA, or peripheral vascular disease
- SBP > 140/90 at two months prior to study enrollment
- Diabetes mellitus requiring insulin therapy
- The following laboratory parameters at the Screening visit
- Neutropenia (absolute neutrophil count < 1,500/microliter [ L]);
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- Thrombocytopenia (platelets < 100,000/ L);
- Anemia (hemoglobin < 8 g/dL);
- Greater than or equal to 3 times the upper limit of normal (ULN) for either of the following liver function tests (LFTs): aspartate transaminase (AST) or alanine transaminase (ALT);
- Renal insufficiency (serum creatinine> 2.0 mg/dL)
- Purified protein derivative (PPD) test of > 5 mm induration regardless of prior BacilleCalmette Guerin vaccine administration or positive QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT) without documentation of completed treatment or evidence of ongoing treatment of latent tuberculosis (TB) for 30 days. Subjects with active TB infection are excluded.
- History of positive PPD, positive QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT), or chest x-ray findings indicative of prior TB infection, without documentation of either treatment for TB infection or chemoprophylaxis for TB exposure
- Prednisone dose > 10 mg/day (or equivalent dose of another corticosteroid) within 1 month of randomization
- Presence of open leg ulcers
- Chronic or persistent infection including but not limited to human immunodeficiency virus [HIV],hepatitis B, hepatitis C, listeriosis, TB, or other opportunistic infection)
- Active infection or severe infections requiring hospitalization or treatment with intravenous(IV) antibiotics, IV antivirals, or IV antifungals within 30 days prior to randomization, or oral antibiotics, oral antivirals, or oral antifungals within 14 days prior to randomization
- Receipt of a live vaccine within 4 weeks prior to randomization
- History of malignancy within the past 5 years other than treated localized carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell skin carcinoma
- Any medical condition, such as uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, known coronary artery disease or known significant cardiac arrhythmias or severe congestive heart failure (New York Heart Association classes III or IV), recent cerebrovascular accidents, severe, progressive or uncontrolled neurological disease, and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the protocol
- Women of childbearing potential who are sexually active and who do not agree to practiceone of the following methods of contraception during the duration of the study
- condoms, sponge, foams, jellies, diaphragm or intrauterine device;
- oral or parenteral contraceptives for 2 months prior to study product administration;
- a vasectomized partner;
- abstinence
- Pregnant (all women of childbearing potential must have a negative serum pregnancy test) or breastfeeding
- Any investigational agent within the earlier of 4 weeks or 5 half-lives prior to randomization
- History of drug or alcohol abuse within 6 months prior to randomization
- Known allergy or hypersensitivity to any study products
- Any psychiatric disorder that prevents the subject from providing informed consent
- Inability or unwillingness to follow the protocol
- Any condition or treatment, which in the opinion of the investigator, places the subject at an unacceptable risk as a participant in the trial
- Any individual who plans to start or stop or change the dose of lipid lowering medication,antihypertensive medication, NSAIDS, Cox-2 inhibitors, aspirin within 1 month of the study or during the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California San Francisco/San Francisco General Hospital
San Francisco, California, 94110
About this study
Official title: Adalimumab to Mitigate Cardiovascular Risk in RA Patients With Well-Controlled Joint Disease
Rheumatoid arthritis patients are at increased risk of cardiovascular disease because of systemic inflammation that can persist even in patients with well-controlled joint disease. We hypothesize that adding an anti-tumor necrosis factor medication, adalimumab, to standard non-biologic therapy for rheumatoid arthritis will improve endothelial function (reduce cardiovascular risk) in these patients. The design of the trial is as follows: 18 month prospective, randomized, double-blind crossover trial comparing the addition of adalimumab to the addition of placebo. The primary endpoint is a change in endothelial cell function, as detected by brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo.
Read the detailed description
Excess mortality associated with RA is due largely to CVD that is not explained by traditional risk factors. Although articular manifestations usually dominate the clinical picture, RA is a systemic inflammatory disease, and systemic inflammation is the thought to be the underlying mechanism responsible for the increased CVD risk associated with RA. Because chronic inflammation can persist in treated RA patients with little or no clinically detectable joint inflammation, treatment to targets based largely on clinically measured joint activity may not adequately suppress the systemic inflammation associated with progression of atherosclerosis. The ACR recommends treatment to a therapeutic target of low disease activity as determined by standardized clinical assessments. We hypothesize that treated RA patients who have reached this ACR target of low disease activity nonetheless have persisting systemic inflammation that contributes to atherogenesis. We further hypothesize that acceleration of RA-directed therapy with systemic anti-inflammatory treatments (TNF inhibition) in patients with low disease activity will improve endothelial function, reduce vascular inflammation and improve the functionality of HDL particles, key biological features in the progression of atherosclerosis and its clinical manifestations.
Trial design: Prospective, randomized, double-blind crossover trial comparing the addition of adalimumab to the addition of placebo.
Study population: 60 RA patients on non-biological DMARDs with low disease activity as determined by a standardized clinical assessment (Disease Activity Score 28 joints [DAS28] < 3.2).
Primary endpoint: Primary endpoint is change in endothelial cell function, as detected by brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo. We postulate that anti-TNF therapy with adalimumab will lead to an absolute increase of 2% in FMD, which typically translates into a 15% reduction in cardiovascular event rates.
- Conditions
- Rheumatoid Arthritis, Cardiovascular Disease
- Being tested
- Adalimumab, Placebo
- Keywords
- rheumatoid, arthritis, cardiovascular, adalimumab, tnf, biologic
- Medical subject headings
- Arthritis, Rheumatoid, Cardiovascular Diseases, Arthritis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AdalimumabDrug
Also called Humira
Patients will be randomized 1:1 to receive either adalimumab or placebo for the first 26 weeks of the trial, and then after a 26 week washout period, will be crossed over into the other arm (either placebo or adalimumab) for weeks 52-78.
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Adalimumab | Experimental | Active Study Drug is Adalimumab (Humira) which is FDA approved to treat rheumatoid arthritis since 2003. Receives: Drug: Adalimumab |
| Placebo | Placebo comparator | Placebo is inert and matches study drug, including the pre-filled syringe, and is supplied by Abbvie, the study drug manufacturer. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Endothelial Function
The primary endpoint is the change in endothelial cell function, as detected by brachial artery flow-mediated dilitation.
Measured: Weeks 0, 13, 26, 52, 65, 78
Secondary outcomes (1)
Change in vascular inflammation
Vascular inflammation at select body sites will be quantified by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).
Measured: Weeks 0 and 26
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jul 2013 (estimated)
- Study startJul 2013
- Primary completionJul 2017
- Study completionJul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jonathan Graf
- Sponsor type
- University, hospital or other
- Collaborators
- American College of Rheumatology Research and Education Foundation, AbbVie
- Responsible party
- Sponsor-investigator, Jonathan Graf, University of California, San Francisco
- Investigators
- Jonathan Graf, MD, Principal investigator, University of California, San FranciscoPeter Ganz, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01893996
- Sponsor's protocol ID
- 12-09816
- Status last verified
- Apr 2021
- First submitted
- 2 Jul 2013
- Last updated
- 9 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 9 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Adalimumab to Mitigate Cardiovascular Risk in RA Patients With Well-Controlled Joint Disease
- ClinicalTrials.gov ID
- NCT01893996
- Acronym / sponsor ID
- 12-09816
- Conditions
- Rheumatoid Arthritis, Cardiovascular Disease
- Keywords
- rheumatoid, arthritis, cardiovascular, adalimumab, tnf, biologic
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 63 participants (actual)
- Lead sponsor
- Jonathan GrafUniversity, hospital or other
- Collaborators
- American College of Rheumatology Research and Education Foundation, AbbVie
- Study start
- Jul 2013 (actual)
- Primary completion
- Jul 2017 (actual)
- Study completion
- Jul 2017 (actual)
- First posted
- 9 Jul 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Rheumatoid arthritis patients are at increased risk of cardiovascular disease because of systemic inflammation that can persist even in patients with well-controlled joint disease. We hypothesize that adding an anti-tumor necrosis factor medication, adalimumab, to standard non-biologic therapy for rheumatoid arthritis will improve endothelial function (reduce cardiovascular risk) in these patients. The design of the trial is as follows: 18 month prospective, randomized, double-blind crossover trial comparing the addition of adalimumab to the addition of placebo. The primary endpoint is a change in endothelial cell function, as detected by brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo.
Detailed description
Excess mortality associated with RA is due largely to CVD that is not explained by traditional risk factors. Although articular manifestations usually dominate the clinical picture, RA is a systemic inflammatory disease, and systemic inflammation is the thought to be the underlying mechanism responsible for the increased CVD risk associated with RA. Because chronic inflammation can persist in treated RA patients with little or no clinically detectable joint inflammation, treatment to targets based largely on clinically measured joint activity may not adequately suppress the systemic inflammation associated with progression of atherosclerosis. The ACR recommends treatment to a therapeutic target of low disease activity as determined by standardized clinical assessments. We hypothesize that treated RA patients who have reached this ACR target of low disease activity nonetheless have persisting systemic inflammation that contributes to atherogenesis. We further hypothesize that acceleration of RA-directed therapy with systemic anti-inflammatory treatments (TNF inhibition) in patients with low disease activity will improve endothelial function, reduce vascular inflammation and improve the functionality of HDL particles, key biological features in the progression of atherosclerosis and its clinical manifestations.
Trial design: Prospective, randomized, double-blind crossover trial comparing the addition of adalimumab to the addition of placebo.
Study population: 60 RA patients on non-biological DMARDs with low disease activity as determined by a standardized clinical assessment (Disease Activity Score 28 joints [DAS28] < 3.2).
Primary endpoint: Primary endpoint is change in endothelial cell function, as detected by brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo. We postulate that anti-TNF therapy with adalimumab will lead to an absolute increase of 2% in FMD, which typically translates into a 15% reduction in cardiovascular event rates.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Adalimumab | Experimental | Drug: AdalimumabActive Study Drug is Adalimumab (Humira) which is FDA approved to treat rheumatoid arthritis since 2003. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo is inert and matches study drug, including the pre-filled syringe, and is supplied by Abbvie, the study drug manufacturer. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Subject must be able and willing to give written informed consent and comply with the requirements of the study protocol.
- Diagnosis of Rheumatoid Arthritis by ACR 1987 or ACR/EULAR 2010 criteria.
- Low RA disease activity as defined by DAS28 < 3.2
- No anti-TNF medication or other biologic agent (abatacept, rituximab, or tocilizumab) within the 12 months prior to enrollment.
- If taking methotrexate, then on a stable dose between 7.5 mg and 25 mg (PO or SQ) weekly for at least 3 months prior to randomization. If on a DMARD other than methotrexate, then that DMARD must be at a stable therapeutic dose for at least 3 months prior to randomization.
Key exclusion criteria (32 listed)
- Use of an anti-TNF or other biologic medication (Including but not limited to abatacept, rituximab, or tocilizumab) within the previous 12 months.
- Prior history of MI, CVA, CABG, PTCA, or peripheral vascular disease
- SBP > 140/90 at two months prior to study enrollment
- Diabetes mellitus requiring insulin therapy
- The following laboratory parameters at the Screening visit
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AdalimumabAlso: HumiraPatients will be randomized 1:1 to receive either adalimumab or placebo for the first 26 weeks of the trial, and then after a 26 week washout period, will be crossed over into the other arm (either placebo or adalimumab) for weeks 52-78. | Drug | Adalimumab |
| Placebo | Drug | Placebo |
Primary outcome
Change in Endothelial Function
Time frame: Weeks 0, 13, 26, 52, 65, 78
The primary endpoint is the change in endothelial cell function, as detected by brachial artery flow-mediated dilitation.
1 secondary outcome
Change in vascular inflammation
Time frame: Weeks 0 and 26
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Apr 2021.
- UCSF Division of Rheumatology: Clinical \& Epidemiological ResearchLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jonathan Graf, MD principal investigator
University of California, San Francisco
Peter Ganz, MD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Adalimumab in people with Rheumatoid Arthritis and Cardiovascular Disease, run by Jonathan Graf at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Endothelial Function (time frame: Weeks 0, 13, 26, 52, 65, 78). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Apr 2021.