Randomised trial optimising COVID-19 vaccination in patients with chronic health conditions and a poor response to standard vaccinatio

Phase 3

Completed

• Conditions: Patients with 1) solid cancer; 2) lymphoid malignancies; 3) immune-mediated rheumatic diseases; 4) end stage kidney disease; 5) liver disease; 6) inflammatory bowel disease on immune suppressive therapy; 7) haematopoietic stem cell transplant; and 8) primary immunodeficiency who have received two doses of SARS-CoV-2 vaccine but have proven inadequate response to the SARS-CoV-2 vaccine; Infections and Infestations; COVID-19 (SARS-CoV-2 infection)

• Registration Number: ISRCTN15354495
• Lead Sponsor: niversity of Birmingham

Brief Summary

2024 Results article in https://doi.org/10.1016/S2665-9913(24)00065-1 (added 20/08/2024)

Detailed Description

Not available

Study Timeline

• Study Start: 2021-07-26
• Study Completion: 2024-08-20
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 804

Inclusion Criteria

1. Aged =18 years
2. Have an inadequate response to two doses of SARS-CoV-2 vaccine measured at least 14 days after receipt of the second vaccine, defined by SARS-CoV-2 spike antibody response. An inadequate response is defined as:
2.1. Antibody non-response: SARS-CoV-2 anti-spike antibodies below the level of detection using the PHE Roche platform [or equivalent] =8 AU/ml, or
2.2. Antibody low-response: SARS-CoV-2 anti-spike antibodies >8 and <400 AU/mL using the Roche platform [or equivalent])
2.3. There is no agreed international/WHO cut off for titres of AU following vaccination and serologic assessment. As such, the low responder status for OCTAVE-DUO eligibility is by definition arbitrary. We have examined the serology levels obtained in the OCTAVE study, compared with PITCH (health care workers without vulnerable conditions) and elected to choose a titre that equates to approximately 30% of the OCTAVE population – this equates to approx. 400 AU hence this selection for this part of the eligibility criteria. Since in practice all vulnerable groups will receive a re-boost in due course, by choosing the lowest tertile for evaluation of enhancement of response, we are maximising the pragmatic value of the study in terms of policy advice, and determination of the magnitude of the immune response, representing our primary outcome. Moreover, we are thereby ensuring rapid and representative recruitment from the variety of vulnerable patient groups in the study protocol.
3. Anticipated life expectancy of 6 months or greater.
4. Fall into one (or more) of the following patient cohorts who will meet disease-relevant classification, disease state, and staging according to established international standards:
4.1. Diagnosed with any of the following solid cancers:
4.1.1. Breast
4.1.2. Lung
4.2. Diagnosed with any of the following lymphoid malignancy categories:
4.2.1. Aggressive B-NHL
4.2.2 Chronic lymphocytic leukemia (CLL)
4.2.3. Hodgkin Lymphoma
4.2.4. Indolent B NHL (except CLL and small lymphocytic lymphoma [SLL])
4.2.5. Myeloma
4.3.Diagnosed with the following rheumatic/inflammatory conditions:
4.3.1. Rheumatoid arthritis
4.3.2. Psoriatic arthritis
4.3.3. Seronegative arthritis
4.3.4. Spondyloarthritis
4.3.5. ANCA-associated vasculitis
4.3.6. Systemic lupus erythematosus (SLE)
4.3.7. Psoriasis
4.3.8. Crohn’s disease/ulcerative colitis
4.3.9. Autoimmune hepatitis
4.4. Diagnosed with the following chronic renal conditions:
4.4.1. End-stage kidney disease secondary to any cause
4.4.2. Renal transplant following end-stage kidney disease
4.5. Diagnosed with the following chronic liver conditions:
4.5.1. Liver cirrhosis
4.5.2. Liver transplantation
4.6. Chronic liver disease (of any stage) on immune suppressive therapy
4.6.1. Diagnosed with gastrointestinal disease and on immune suppressive therapy
4.7. Diagnosed with primary antibody deficiency: defined as any patient who is on immunoglobulin replacement therapy or any patient with an IgG <4g/l and on prophylactic antibiotics.
4.8. Haematopoietic stem cell transplant:
4.8.1. Previously treated with autologous or allogenic haematopoietic stem cell transplant for any indication and with any conditioning regimens and intensities
4.8.2. Previously treated with CAR-T cell therapies
5. Participant is willing and able to comply with trial requirements.
6. For the randomised sub-study only, female participants of childbearing potential* must be willing to ensure that they or their par

Exclusion Criteria

1. Receipt of any vaccine within 30 days before trial entry, with the exception of a SARS-CoV2 vaccine which is allowed =14 days prior, or a flu vaccination which is allowed =7 days prior
2. For aggressive B-NHL or Hodgkin lymphoma only, participants on active systemic treatment or within 4 weeks of completion of systemic treatment
3. Any known contraindications as specified in the applicable product information (see Section 7.1) including but not limited to:
3.1. Known allergy or hypersensitivity to any of the trial IMPs or any of the trial drug excipients
3.2. History of anaphylaxis
4. In the judgement of the Investigator the patient is unsuitable to participate in the trial or is unlikely to comply with trial procedures
5. For the randomised sub-study only, patients who are pregnant at trial entry or planning to become pregnant within 3 months after re-vaccination

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1. Anti-spike SARS-CoV-2 antibody and T cell responses to SARS-CoV-2 peptides following Pfizer and Moderna re-boost vaccinations will be measured before the re-boost vaccination was given and will be compared with those achieved at day 21 post dose:<br>1.1. Anti-spike SARS-CoV-2 antibodies following re-boost vaccination will be measured using the Roche platforms by the Public Health England (PHE) Laboratories at Porton Down. The Roche assays will measure the presence and amount of serum antibodies to both the spike (S) and the nucleocapsid (N) antigens of SARS-CoV-2. This assay will enable the discrimination of antibody responses to SARS-CoV-2 that results from vaccination and/or SARS-CoV-2 infection.<br>1.2. T cell responses to SARS-CoV-2 peptides following re-boost vaccination will be measured using the Oxford Immunotec modified T-spot discovery SARS-CoV-2 assay. This IFN? ELISpot assay will provide insights into the participants’ reactivity to SARS-CoV-2 s1, s2, nucleocapsid and membrane peptides.

Secondary Outcome Measures

Name	Time	Method
1. In a sub-set of participants with lymphoid malignancies, measure the change in vaccine-specific immunogenicity in response to vaccination (as defined for the primary outcome) with Pfizer, Moderna or Novavax vaccines. <br>2. In all patient groups, we will assess the capacity of re-boost vaccine-induced SARS-CoV-2 antibodies to neutralise/block SARS-CoV-2 infection using IgG (pseudo)neutralisation assays (CE marked Menarini Diagnostics surrogate neutralisation assay) and measured in samples collected before the re-boost vaccination was given and compared with those achieved at day 21 post-dose.