| Eligibility |
Inclusion Criteria:
- Able to understand the purpose and the procedures involved in this study and sign the
informed consent form.
- Male or non-pregnant female adults, 18-45 years of age inclusive.
- Non-smoker and in good general health, as determined by medical screening evaluation,
performed by PI or delegated sub-investigator no greater than 28 days before the first
dose in the form of medical history, clinical laboratory tests and physical
examination.
- Normal Electrocardiogram (ECG).
- Echocardiogram (ECHO) that is normal or with findings that are considered trivial and
clinically insignificant such as 'Clinically insignificant/trivial mitral
regurgitation
- Women must agree not to become pregnant during the trial. If they are sexually active,
they must use an effective method of birth control, e.g. insertable, injectable,
transdermal, or combination oral contraceptive approved by Health Canada combined with
a barrier contraceptive and have negative results on a serum or urine pregnancy test
done before administration of study medication.
- Intention to reside in the geographical area for next 10 months and not intending to
travel overseas for at least 30 days following the last study vaccine administration.
- Agree not to participate in any other clinical trial during the trial.
- Agree not to donate blood for the duration of the trial.
- Agree to restrain from intensive physical exercise i.e. exercise that varies
significantly from an everyday exercise routine, 3 days before and after (± 3 days)
administration of each dose, including each interim visit for blood sample collection.
- Up to date on seasonal influenza vaccine and recommended COVID-19 vaccines and booster
doses at the time of study enrolment.
Exclusion Criteria:
1. Personal or family history of post-streptococcal disease (rheumatic fever or
glomerulonephritis), or collagen-vascular disease
2. Evidence of increased cardiovascular disease risk (defined as >10%, 10- year risk
using Framingham score - see Appendix 5). Risk factors include sex, age, systolic
blood pressure (mm Hg), smoking status, body mass index (BMI, kg/m2), reported
diabetes status and blood pressure
3. Previous use of phentermine (appetite suppressant of the amphetamine and
phenethylamine class), fenfluramine or dexfenfluramine known as Fen-Phen, anti-obesity
medications (possible association with cardiac valvular abnormalities);
4. Clinical diagnosis or evidence of recent group A streptococcal infection as measured
by anti-streptolysin O or anti-DNase B levels exceeding 200 units;
5. Positive group A streptococcus throat culture at screening or rapid antigen test on
day of study product administration;
6. Presence of significant acute infection requiring systemic antibiotic treatment within
the 14 days prior to each product administration;
7. Pregnant or breast feeding (all women will have a negative pregnancy test result prior
to each study product administered);
8. Immunized or intent to immunize with any vaccine or investigational agents within 30
days prior to enrolment through to 30 days following the last study vaccine
administration, with the exception of licensed inactivated influenza vaccines and
COVID-19 vaccines;
9. Past significant reaction following any previous vaccination;
10. History of hypersensitivity to any diphtheria toxoid or CRM197 containing vaccine;
11. Presence of acute infectious disease or fever (e.g., sub-lingual temperature 38.5°C)
within the five days prior to study product administration;
12. Presence of current or suspected serious chronic diseases such as cardiac or
autoimmune disease (HIV or other immunodeficiencies), insulin dependent diabetes,
progressive neurological disease, severe malnutrition, acute or progressive hepatic
disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma,
epilepsy or obsessive-compulsive disorder, skin carcinoma excluding non-spreadable
skin cancers such as basal cell and squamous cell carcinoma;
13. Evidence and any history of leukaemia, lymphoma, or neoplasm;
14. Presence or suspicion of impaired immune system function. Currently receiving or
having within the past three years received immunosuppressive therapy, including
systemic steroids, ACTH or inhaled steroids in dosages that are associated with
hypothalamic-pituitary-adrenal axis suppression, such as 1mg/kg/day of prednisone or
its equivalent or chronic use of inhaled high potency corticosteroids [budesonide 800
µg per day or fluticasone 750 µg];
15. Received blood, blood products or a parenteral immunoglobulin preparation in the past
12 weeks;
16. Evidence of bleeding diathesis or any condition that may be associated with a
prolonged bleeding time;
17. Known inherited genetic anomaly (known as cytogenic disorders) e.g., Down's syndrome;
18. Evidence of any condition that, in the opinion of the clinical investigator, might
interfere with the evaluation of the study objectives or pose excessive risks to
participants;
19. Findings of definite, probable, or possible rheumatic heart disease (RHD), definite or
probable acute rheumatic fever (ARF).
20. Inadequate echocardiographic windows for assessment.
21. Echocardiographic findings such as: Cardiac Chambers: left ventricular dilatation
(based on LV diameter > 29mm/m2 to BSA); left ventricular dysfunction (Ejection
Fraction < 50%; left ventricular hypertrophy (LV wall thickness > 11mm); Right
ventricular dysfunction or dilatation (Subjective assessment);
22. Cardiac Valves/Haemodynamic Findings: Clinically significant mitral regurgitation
defined: at the discretion of the cardiologist and/or effective regurgitant orifice
area of >10mm2; Any degree of valvular stenosis or left ventricular outflow tract
obstruction; Pulmonary hypertension (defined as an estimated right ventricular
systolic pressure of >30 mmHg, calculated using the peak tricuspid regurgitant jet
velocity method);
23. Any aortic regurgitation;
24. Pericardium: greater than trivial pericardial fluid (trivial defined as < 5mm and not
circumferential);
25. Pre-existing significant structural valve disease (for example, but not limited to
bicuspid aortic valve regardless of haemodynamic effect, mitral valve prolapse
regardless of severity of regurgitation, pulmonary stenosis);
26. Other significant congenital lesions (for example, but not limited to aortic
coarctation, septal defect, excluding patent foramen ovale (NOTE: findings considered
normal developmental variation, specifically including patient foramen ovale and
prominent Eustachian valve will not be considered exclusion criteria;
27. Clinical or sub-clinical acute post-streptococcal glomerulonephritis (APSGN),
28. Clinically significant abnormal laboratory results e.g., CBC with differential and
platelets, AST, ALT, creatinine, fasting blood sugar, electrolytes (including sodium,
potassium, chloride, and bicarbonate);
29. The participant has a diagnosis of schizophrenia, bi-polar disease, or other severe
(disabling) chronic psychiatric diagnosis;
30. The participant has been hospitalized within the past 5 years prior to enrollment for
psychiatric illness, history of suicide attempt or confinement for danger to self or
others;
31. The participant is receiving psychiatric drugs but their psychiatric conditions is not
stabilized. Participants who are receiving a single antidepressant drug and are stable
for at least 3 months prior to enrollment without decompensating are allowed
enrollment into the study; *aripiprazole, clozapine, ziprasidone, haloperidol,
molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone,
mesoridazine, quetiapine, trifluoperazine, trifluopromazine, chlorprothixene,
chlorpromazine, perphenazine, olanzapine, carbamazepine, divalproex sodium, lithium
carbonate or lithium citrate. This is not an absolute contra-indication and clinician
judgment will be used to assess the likelihood that this will compromise trial
participation and follow-up.
32. The participant has a history of alcohol or drug abuse in the 5 years prior to
enrollment. This is not an absolute contra-indication and clinician judgment will be
used to assess the likelihood that this will compromise trial participation and
follow-up.
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