Clinical trial NCT04754698: COVID-19 CoronaVac in Patients With Autoimmune Rheumatic Diseases and HIV/AIDS
Official title: Immunogenicity and Safety of the CoronaVac Vacccine in Patients With Autoimmune Rheumatic Diseases and People Living With HIV/AIDS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatic Disease
HIV Infections
AIDS
Safety Issues
Immunogenicity
COVID-19
Keywords: CoronaVac
Vaccine
Rheumatic disease
Systemic lupus erythematosus
Rheumatoid arthritis
HIV
AIDS
Safety
Immunogenicity
COVID-19
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
First posted: 2021-02-15
Enrollment: 2196
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Study consisting of 3 arms, all of which will receive CoronaVac: patients with rheumatic diseases, PLWHA, and healthy controls. Also, in an exploratory, post hoc, substudy nested within the trial, 2 other arms will receive exercise or no intervention 1 hoour before the third dose.
Primary purpose: PREVENTION

Brief summary: Patients with chronic rheumatic diseases (such as systemic lupus erythematosus \[SLE\], rheumatoid arthritis \[RA\], ankylosing spondylitis \[AS\], juvenile idiopathic arthritis \[JIA\], poly/dermatomyositis \[PM/DM\], systemic sclerosis \[SSc\], systemic vasculitis, and primary Sjögren's syndrome \[pSS\]) are particularly susceptible to infectious diseases due to autoimmune disorder itself and its treatment (immunosuppressive therapies). Similarly, people living with HIV/AIDS (PLWHA) are predisposed to infections by different agents.

The current 2019 Coronavirus Disease Pandemic-19 (COVID-19), caused by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) began in December 2019 in Wuhan, China, and quickly became a global health and economic emergency by taking to an unprecedented burden on health systems around the world.

However, SARS-Cov-2 infection raised particular concern in patients with autoimmune rheumatic diseases (DRAI) since, due to chronic inflammatory immune dysregulation and the regular use of immunosuppressive drugs, these patients are considered to be at high risk of contracting SARS-CoV-2 and potentially evolving to a worse prognosis.

The overlap between the COVID-19 pandemic and the HIV/AIDS pandemic also poses an additional challenge, as the impact of co-infection is not yet fully known. The response to vaccines for other agents, however, has already been described as compromised in PLWHA.

Vaccination is the most effective preventive measure to control the spread of coronavirus and to reduce associated complications. Usually, live or attenuated vaccines are not recommended for patients with chronic rheumatic diseases using immunosuppressants. However, immunization with inactivated agents is strongly indicated, resulting, in general, in good immunogenicity and adequate vaccine safety, as well as without relevant deleterious effects on diseases.

Vaccine efficacy studies are needed to verify the immunogenicity of the vaccine against COVID-19 in immunosuppressed patients with rheumatological disease and those with HIV-related disease considering the risk of greater severity. In addition, it is important to assess the safety of the vaccine in this population as well as the possibility of reactivating the rheumatological disease itself.

The present study will evaluate the safety and immunogenicity of the CoronaVac (Coronavirus vaccine, Sinovac Biotech Ltd.) in patients with rheumatic diseases and PLWHA

Detailed description: A sample of 1254 patients with rheumatic diseases and 542 healthy controls matched for age and sex was calculated as follows.

1.A) Evaluation of patients with SLE compared to a healthy control group matched for age and sex. The investigators calculated 74 patients in each arm, which will be compared independently to the healthy control group:

* 74 SLE patients treated with hydroxychloroquine alone;
* 74 SLE patients with mild immunosuppression (azathioprine or methotrexate and prednisone \<10 mg/day);
* 74 patients with moderate to severe immunosuppression (mycophenolate mofetil or cyclophosphamide and/or prednisone \>10 mg/day);
* 50 patients with belimumab (convenience sample). Total: 272 SLE patients and 74 healthy controls.

  1.B) Evaluation of RA patients compared to healthy controls matched for age and sex. The investigators calculated 61 patients in each arm, which will be independently compared to the control group:
* 61 RA patients only with conventional synthetic disease-modifying drugs (DMARDs);
* 61 RA patients with biological disease-modifying drugs (bDMARDs) with anti-TNF (anti-tumor necrosis factor) action;
* 61 RA patients with bDMARDs with non-anti-TNF action and with impact on the production of immunoglobulins (abatacept and rituximab);
* 61 RA patients with bDMARDs with anti-IL-6 (anti-interleukin-6) action (tocilizumab) and synthetic drugs with anti-JAK (anti-janus kinase) action (tofacitinib).

Total: 244 RA patients vs. 61 healthy controls. 1.C) Evaluation of the interruption of the use of methotrexate (MTX) for 4 weeks from the first dose of vaccination in RA patients. Inclusion: patients using MTX in a stable dose for at least 4 weeks, prednisone maximum dose of 7.5 mg/day, in association or not with other drugs, to be randomized in two arms: one that keeps the therapy stable and the other which suspends MTX for 4 weeks from the first dose. The investigators calculated 96 patients in each arm:

* 96 MTX patients who will not have their therapy changed;
* 96 MTX patients who will stop only MTX on the day of vaccination for 4 weekly applications.

Total: 192 RA patients.

1.D) Evaluation of patients with AS/psoriatic arthritis compared to a healthy control group matched for age and sex. The investigators calculated 136 patients in each arm, 136 with synthetic DMARDs and 136 with bDMARDs, to be compared with 136 healthy controls matched for age and sex.

Total: 272 patients with AS/psoriatic arthritis vs. 136 healthy controls.

1. E) A convenience sample of 250 (50 in each group) patients with other rare rheumatic diseases (SSc, PM/DM, pSS, systemic vasculitis, and primary antiphospholipid antibody syndrome) being followed up in Rheumatology Division (HCFMUSP) will be vaccinated and matched using the pool of controls from the other samples.

   Controls: 271 healthy controls matched for age and sex will be included according to the need for controls for SLE (n = 74), RA (n = 61) and AS/psoriatic arthritis (n = 136) will be selected to receive the vaccine at HCFMUSP.
2. PEOPLE LIVING WITH HIV/AIDS (PLWHA) The investigators considered the immunogenicity of the vaccine for Yellow Fever as a parameter in a previous study carried out by our group. The response found was p1 = 92% induction of neutralizing antibodies in PLWHA. Considering the 1:1 ratio between vaccinated and controls, alpha error of 5% with 80% power, the sample size will be 271 vaccinated in the PLWHA group and 271 in the control group, with an effect size of 0.25.

Total population: 1254 ARD patients + 542 controls + 271 patients in PLWHA group = 2067 patients.

In addition to a symptom diary (provided to research subjects on the 1st and 2nd vaccine doses), all patients and controls were instructed to contact the researchers by email, WhatsApp, and telephone in case of adverse effects or symptoms of COVID. In cases of suspected COVID, RT-PCR and genotyping are being performed.

Extension phase of the project

There are clinical trials using a booster dose (third dose of mRNA vaccine against COVID-19) in renal transplant recipients, who similarly to patients with autoimmune rheumatic diseases (ARDs), had high rates (about 40%) of poor humoral response. Antibody titers increased after the third dose in one third of patients who had negative response and in all patients who had low antibody titers. In addition, patients on therapy with specific drugs (tacrolimus, mycophenolate and glucocorticoids) were less likely to develop anti-SARS-CoV-2 antibodies than those treated with other regimes. No serious adverse events were observed after the third dose (Werbel et al., 2021; Benotmane et al., 2021).

Therefore, we consider a booster dose (third dose of Sinovac-CoronaVac) for ARDs patients 6 months after the primary vaccination. The monitoring of anti-SARS-CoV-2 humoral response \[anti-SARS-CoV-2 IgG seroconversion and neutralizing antibody (NAb)\] will be carried out immediately before the third dose and 6 weeks after.

This extension phase of the study was approved by the National Research Ethics Committee (Comissão Nacional de Ética em Pesquisa) (4.951.263). Only participants (patients/controls) who agree to participate in the extension phase of the study will be included according to the signed updated informed consent form. The expected sample is 1300 patients and 340 controls.

Guidance on use of immunosuppressive medications during the vaccination period will be according to the updated recommendations of the American College of Rheumatology (ACR) (https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-RheumaticDiseasesSummary.pdf).

Similar to the first phase of the study, in addition to a symptom diary (provided to research subjects on the 3th vaccine doses), all patients and controls were instructed to contact the researchers by email, WhatsApp, and telephone in case of adverse effects or symptoms of COVID. In cases of suspected COVID, RT-PCR and genotyping are being performed.

In an exploratory substudy nested within this phase 4 trial, a subsample composed by AS/psoriatic arthritis (n=60) will be randomly assigned to receive exercise or nothing 1 hour before vaccination, under the working hypothesis that exercise may boost immune responses to the vaccine, wich would benefit immunocompromised patients. The exercise session will be conducted by experienced exercise physiologists and will comprise a brief specific warm-up and 3 unilateral resistance exercises (lateral raise, biceps curl and overhead extension) in the left arm (the same arm used for vaccination). The exercises will be performed using dumbbells, with eccentric and concentric contractions (4 sets of 8-12 repetition maximum). Interval between exercises and sets will be 30 seconds. The total duration of the exercise session will be approximately 20 minutes. Thirty minutes after the end of the exercise session, patients will receive the vaccine in the same arm (i.e., left arm). Immediately, 24h and 48h after the exercise session, local pain (muscle soreness) in the exercised arm will be assessed by visual analogue scale (0 \[no pain\] to 100 \[worst possible pain\]). Exercise-induced edema will be determined by circumference measures of the biceps. Participants will also report self-perceived exertion after exercise using the Borg scale. Blood sample to assess immunogenicity (primary outcome) will follow the same schedule proposed in the phase 4 trial. Control group will receive no intervention and will follow the vaccination scheme adopted in the phase 4 trial.

Amendment to the extension phase of the project

Rationale: There are clinical trials comparing homologous vaccine scheme (two first doses) against COVID-19 versus heterologous immunization suggesting that the latter was well tolerated and improved immunogenicity healthy individuals (Hillus et al., 2021). In animal models, there is evidence that application of a third vaccine dose (booster) with an mRNA vaccine after two vaccine doses of inactivated against COVID-19 induce a relatively higher level of neutralizing antibodies and T cell response (Zhang et al., 2021). Thus, we will include the following extension analyses in this project:

1. For patients and controls without humoral response (anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies) after the 3rd dose of CoronaVac vaccine, a booster dose with the available heterologous vaccine will be given as per the Plan National Vaccination of COVID-19 in ARD patients.
2. A new serology analysis will be performed (anti-SARS-CoV-2 S1/S2 IgG and neutralizing antibodies) 4-8 weeks after the heterologous vaccine booster. Immunogenicity will be assessed through seroconversion rates of total IgG antibodies against S1 and S2 antigens and neutralizing antibodies.
3. In addition, the participants will be instructed to write down in a diary standardized changes that occur and to contact investigators by e-mail or WhatsApp.
4. The updated recommendations of the American College of Rheumatology (ACR) regarding to the use of immunosuppressive medications during the vaccination period will be followed (https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-RheumaticDiseasesSummary.pdf).

This amendment to the extension phase of the project was approved by the National Research Ethics Committee (Comissão Nacional de Ética em Pesquisa) (5.014.175). Only participants (patients/controls) who agree to participate in this amendment to extension phase of the study will be included according to the signed updated informed consent form.

Eligibility criteria: Inclusion Criteria:

* RA patients according to the classification criteria of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR).
* Patients with axial spondyloarthritis (ASAS criteria 2009) and psoriatic arthritis (CASPAR 2012 criteria).
* SLE patients according to the SLICC classification criteria.
* SSc patients according to the ACR preliminary criteria.
* Patients with inflammatory myopathies according to the Bohan and Peter's criteria.
* Patients with primary vasculitis.
* Patients with pSS (2002 American-European Consensus group criteria and/or 2016 classification criteria of the EULAR/ACR.
* Patients with primary APS (primary antiphospholipid syndrome) (Sydney classification criteria).
* Patients with HIV-related illness.

Exclusion Criteria:

* History of anaphylactic response to vaccine components.
* Acute febrile illness.
* Guillain-Barré syndrome, decompensated heart failure (class III or IV), demyelinating disease.
* History of live virus vaccine up to 4 weeks before, virus vaccine inactivated up to 2 weeks before.
* History of having received blood products up to 6 months before the study.
* Individuals who do not accept to participate in the study and/or whose guardians do not agree to participate in the study.
* Hospitalized patients.
* Patients with severe conditions requiring hospitalization.

Primary outcomes:
measure: Immunogenicity 1
timeFrame: 8 months
measure: Immunogenicity 2
timeFrame: 8 months
Secondary outcomes:
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: University of Sao Paulo General Hospital
state: SP
Study officials:
affiliation: University of Sao Paulo General Hospital
name: Kallas, MD, PhD
role: STUDY_CHAIR
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