E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The aim of the study is to evaluate pneumococcal vaccination strategy with PPSV23 and PCV13 in patients with chronic lymphocytic leukemia (CLL) initially randomized in a clinical study. |
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E.1.1.1 | Medical condition in easily understood language |
Chronich Lymphocytic Leukemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
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 |
1) To determine and compare the sustained immune response 3-5 years after vaccination with a single dose of 13-valent pneumococcal conjugated vaccine (PCV13, Prevenar13®) or conventional 23-valent capsular polysaccharide vaccine (PPSV23, Pneumovax®) in the cohort from our previous randomized phase III trial.
2) To study the effect of revaccination with PCV13 in both vaccination groups and to investigate if there is an additive effect of another dose of PCV13 in patients with CLL. For the group that did not receive PPSV23 in the randomized trial, this vaccine will be given to broaden the serotype response and determine the additive effect after PCV13 vaccination.
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E.2.2 | Secondary objectives of the trial |
1) To determine the prevalence of pneumococcal colonization in nasopharynx. 2) To determine the incidence of invasive pneumococcal disease in the study cohort. 3) To study the effect of pneumococcal revaccination on immune cells and cytokine levels. 4) To compare the sustained immune response between CLL patients and immunocompetent controls, 3-5 years after vaccination with PCV13 and PPSV23. 5) To compare the immune response between CLL patients and immunocompetent controls, after revaccination with one dose of PCV13. 6) To compare the prevalence of pneumococcal colonization and incidence of invasive pneumococcal disease between CLL patients and immunocompetent controls after vaccination and revaccination. 7) To compare the effect of pneumococcal revaccination on immune cells and cytokine levels between CLL patients and immunocompetent controls. 8) To compare the immune response after SARS-CoV-2 vaccination to the immune response after pneumococcal revaccination.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
CLL patients CLL patients earlier included in the Pneumococcal vaccination study 0887x1-20003 (EudraCT No: 2009-012642-22), who have received either PCV13 or PPSV23 are eligible for evaluation of the long-term immune response. The median age of the patient group was at inclusion 70 years (range 46-87) with an equal number men and women (65/63). The same patients are eligible for revaccination if they do not meet any exclusion criteria. Ongoing or recent CLL specific treatment is not an exclusion criteria.
Controls A control group (n=40) of immunocompetent subjects will be recruited in Region Örebro County. The control group will be matched to the CLL group by age and gender. For inclusion they should have been vaccinated with either PCV13 (n=20) or PPSV23 (n=20) approximately 3-5 years ago and not meet any exclusion criteria. They will subsequently be eligible for long-term immune response and revaccination according to the study protocol. |
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E.4 | Principal exclusion criteria |
CLL patients 1. Patients receiving high dose corticosteroids ( ≥20 mg Prednisolone) or other immunosuppressive drugs that is not part of active CLL treatment 2. Patients who have had an allergic reaction to any vaccination in the past 3. Patients with a positive DAT (Direct Antiglobulin Test) or known present or previous hemolysis, ITP and Guillain-Barre 4. Patients failing to give informed consent 5. Patients with ongoing immunoglobulin therapy 6. Patients with known HIV infection 7. Patients who have received a pneumococcal vaccine outside the study protocol within the last 12 months 8. Active febrile infection 9. Increased bleeding risk due to severe thrombocytopenia or other coagulopathies that would, in the opinion of the investigator, contraindicate intramuscular injection
Controls 1. Serious chronic disorder including chronic obstructive pulmonary disease (COPD) requiring supplemental oxygen treatment, end-stage renal disease, clinically unstable cardiac disease or any other disorder that, in the investigator’s opinion, excludes the subject from participating in the study; 2. Known or suspected immunodeficiency or other conditions associated with immunosuppression including immunoglobulin class/subclass deficiencies with or without substitution treatment, splenectomy in the medical history, generalized malignancy, human immunodeficiency virus (HIV) infection, haematological malignancies, bone marrow or organ transplant in the medical history; 3. Subjects receiving treatment with high dose corticosteroids (≥20 mg Prednisolone) or other immunosuppressive drugs, or planned to receive through study participation; 4. Subjects who have had an allergic reaction to any component of PCV13 in the past; 5. Subjects with known present or previous hemolysis, ITP and Guillain-Barre; 6. Subjects failing to give informed consent; 7. Subjects who have received a pneumococcal vaccine after the primary vaccination aproximately 3-5 years ago; 8. Active febrile infection; 1.9. Increased bleeding risk due to severe thrombocytopenia or other coagulopathies that would, in the opinion of the investigator, contraindicate intramuscular injection (for treatment with oral anticoagulation therapy, see section 7.3).
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E.5 End points |
E.5.1 | Primary end point(s) |
1) To study the long-term immune response between the two groups 3-5 years after vaccination with PCV13 or PPSV23, measured as the proportion of subjects with a positive vaccination response in each of the two groups.
2) To study the short-term immune response 8 weeks and 16 weeks after revaccination of the initial PCV 13 Group A with PCV13/PPSV23 and of the initial PPSV23 Group B with PCV13/PCV13, measured as the proportion of subjects with a positive vaccination response pre- and post- revaccination.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
8 and 16 weeks after revaccination. |
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E.5.2 | Secondary end point(s) |
1) To study the persistent immune response after revaccination in terms of OPA titers 12 months after first dose of revaccination compared to the short-term pre- and post-revaccination sera. 2) To compare ELISA GMCs for each serotype measured 3-5 years after initial vaccination. 3) To compare ELISA GMCs for each serotype measured 8 weeks, 16 weeks and 12 months after revaccination. 4) To study the incidence of IPD during the period from the initial vaccination to maximum five years after the first dose of revaccination. 5) To study the incidence of pneumococcal colonization by culturing of nasopharyngeal swabs at inclusion after 8 weeks, 16 weeks and 12 months. 6) To study the long-term immune response (ELISA and OPA) 3-5 years after vaccination with PCV13 or PPSV23, by comparing CLL patients and controls. 7) To study the short-term immune response (ELISA and OPA) 8 weeks after revaccination with one dose of PCV13, by comparing CLL patients and controls. 8) To study the additive immune response (ELISA and OPA) after a second revaccination dose (PCV13 or PPSV23) of CLL patients in comparison with controls with no second revaccination dose, 16 weeks and 12 months after revaccination. 9) To study the immune response 3-4 weeks, 6-8 weeks, 6 months and 12 months after initial SARS-CoV-2 vaccination in terms of antibody titers/function induced by the vaccine and compare to the immune response after pneumococcal revaccination.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PCV13 or PPSV23 vaccination: 8 weeks, 16 weeks and 12 months after revaccination.
Covid-19 vaccination: 3-4 weeks after each dose and 6 and 12 months after the first Covid-19 vaccination. |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
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 | No |
E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |