Aug 26, 2020
Severity Grading Table (Appendix B of Phase 3 study of Vaccine Candidate for COVID-19)
- Chris Ockenhouse1,
- Chris Gast1,
- Renee Holt1,
- Jorge Flores1
- 1Center for Vaccine Innovation and Access, PATH (Washington D.C. and Seattle, Washington)
- Coronavirus Method Development Community
- PATH
Protocol Citation: Chris Ockenhouse, Chris Gast, Renee Holt, Jorge Flores 2020. Severity Grading Table (Appendix B of Phase 3 study of Vaccine Candidate for COVID-19). protocols.io https://dx.doi.org/10.17504/protocols.io.bj6ckraw
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Created: August 22, 2020
Last Modified: August 26, 2020
Protocol Integer ID: 40868
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Abstract
This is Appendix B of "Phase 3 randomized, double-blinded, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of Vaccine Candidate against COVID-19 in adults > 18 years of age"
This generic Phase 3 protocol was developed by the PATH team with support of the Bill and Melinda Gates Foundation. The aim of the collection is to share recommended best practices in designing and implementing a Phase 3 study of a COVID-19 vaccine candidate. As Phase 3 trials of different Vaccine Candidates proceed around the world, following the same protocols will ensure consistency and comparability of the Phase 3 trial results.
Please note that this is an evolving document, to be versioned and updated, based on community feedback and new data.
Attachments
Guidelines
APPENDIX B: SEVERITY GRADING TABLE
Grading the Severity of Adult Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. This table is available at:https://rsc.niaid.nih.gov/sites/default/files/corrected-grading-table-v-2-1-with-all-changes-highlighted.pdf
| Systemic Illness | Mild (Grade 1) | Moderate (Grade 2) | Severe (Grade 3) | Potentially Life-Threatening (Grade 4) | |
| Illness or clinical AE (as defined according to applicable regulations) | No or minimal interference with usual activities; no medical intervention/ therapy required | Greater than minimal interference with usual activities; no or minimal medical intervention/ therapy required | Marked limitation in ability to perform usual activities; medical intervention/ therapy required | Inability to perform basic functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death |
| Local Reaction to Injectabe Product | Mild (Grade 1) | Moderate (Grade 2) | Severe (Grade 3) | Potentially Life Threatening (Grade 4) | |
| Injection site pain (pain without touching) OR Tenderness (pain when area touched) | Pain/tenderness causing no or minimal limitation of use of limb | Pain or tenderness causing greater than minimal limitation of use of limb | Pain/tenderness causing inability to perform usual activities | Pain/tenderness causing inability to perform basic functions OR Hospitalization indicated | |
| Injection site erythema or induration | 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area | ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area | ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR Secondary infection OR Phlebitis OR Sterile abscess OR Drainage | Potentially life-threatening consequences (e.g., abscess, exfoliative dermatitis, necrosis involving dermis or deeper tissue) | |
| Injection site pruritus | Itching localized to the injection site that is relieved spontaneously or in < 48 hours of treatment | Itching beyond the injection site that is not generalized OR Itching localized to the injection site requiring ≥ 48 hours treatment | Generalized itching causing inability to perform usual social & functional activities | N/A |
| Systemic (General) | Mild (Grade 1) | Moderate (Grade 2) | Severe (Grade 3) | Potentially Life Threatening (Grade 4) | |
| Acute systemic allergic reaction | Localized urticaria (wheals) with no medical intervention indicated | Localized urticaria with medical intervention indicated OR Mild angioedema with no medical intervention indicated | Generalized urticaria OR Angioedema with medical intervention indicated OR Symptomatic mild bronchospasm | Acute anaphylaxis OR Life-threatening bronchospasm OR laryngeal edema | |
| Fever | 37.7 – 38.6°C | 38.7 – 39.3°C | 39.4 – 40.5°C | > 40.5°C | |
| Myalgia (generalized) | Muscle pain causing no or minimal interference with usual social and functional activities | Muscle pain causing greater than minimal interference with usual social and functional activities | Muscle pain causing inability to perform usual social and functional activities | Disabling muscle pain causing inability to perform basic self-care functions | |
| Headache | Symptoms causing no or minimal interference with usual social and functional activities | Symptoms causing greater than minimal interference with usual social and functional activities | Symptoms causing inability to perform usual social and functional activities | Symptoms causing inability to perform basic self-care functions OR Hospitalization indicated OR Headache with significant impairment of alertness or other neurologic function | |
| Chills | Symptoms causing no or minimal interference with usual social and functional activities | Symptoms causing greater than minimal interference with usual social and functional activities | Symptoms causing inability to perform usual social and functional activities | N/A | |
| Fatigue | Symptoms causing no or minimal interference with usual social and functional activities | Symptoms causing greater than minimal interference with usual social and functional activities | Symptoms causing inability to perform usual social and functional activities | Incapacitating symptoms of fatigue or malaise causing inability to perform basic self-care functions |
B. Tables for laboratory abnormalities
The laboratory values provided in the tables below serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
| Serum* | Mild (Grade 1) | Moderate (Grade 2) | Severe (Grade 3) | Potentially Life Threatening (Grade 4)** | |
| Sodium – Hyponatremia mEq/L | 132 – 134 | 130 – 131 | 125 – 129 | < 125 | |
| Sodium – Hypernatremia mEq/L | 144 – 145 | 146 – 147 | 148 – 150 | > 150 | |
| Potassium – Hyperkalemia mEq/L | 5.1 – 5.2 | 5.3 – 5.4 | 5.5 – 5.6 | > 5.6 | |
| Potassium – Hypokalemia mEq/L | 3.5 – 3.6 | 3.3 – 3.4 | 3.1 – 3.2 | < 3.1 | |
| Glucose – Hypoglycemia mg/dL | 65 – 69 | 55 – 64 | 45 – 54 | < 45 | |
| Glucose – Hyperglycemia Fasting – mg/dL Random – mg/dL | 100 – 110 110 – 125 | 111 – 125 126 – 200 | >125 >200 | Insulin requirements or hyperosmolar coma | |
| Blood urea nitrogen BUN mg/dL | 23 – 26 | 27 – 31 | > 31 | Requires dialysis | |
| Creatinine – mg/dL | 1.5 – 1.7 | 1.8 – 2.0 | 2.1 – 2.5 | > 2.5 or requires dialysis | |
| Calcium – hypocalcemia mg/dL | 8.0 – 8.4 | 7.5 – 7.9 | 7.0 – 7.4 | < 7.0 | |
| Calcium – hypercalcemia mg/dL | 10.5 – 11.0 | 11.1 – 11.5 | 11.6 – 12.0 | > 12.0 | |
| Magnesium – hypomagnesemia mg/dL | 1.3 – 1.5 | 1.1 – 1.2 | 0.9 – 1.0 | < 0.9 | |
| Phosphorous – hypophosphatemia mg/dL | 2.3 – 2.5 | 2.0 – 2.2 | 1.6 – 1.9 | < 1.6 | |
| CPK – mg/dL | 1.25 – 1.5 x ULN*** | 1.6 – 3.0 x ULN | 3.1 –10 x ULN | > 10 x ULN | |
| Albumin – hypoalbuminemia g/dL | 2.8 – 3.1 | 2.5 – 2.7 | < 2.5 | -- | |
| Total Protein – hypoproteinemia g/dL | 5.5 – 6.0 | 5.0 – 5.4 | < 5.0 | -- | |
| Alkaline phosphate – increase by factor | 1.1 – 2.0 x ULN | 2.1 – 3.0 x ULN | 3.1 – 10 x ULN | > 10 x ULN | |
| Liver function tests –ALT, AST increase by factor | 1.1 – 2.5 x ULN | 2.6 – 5.0 x ULN | 5.1 – 10 x ULN | > 10 x ULN | |
| Bilirubin – when accompanied by any increase in liver function test increase by factor | 1.1 – 1.25 x ULN | 1.26 – 1.5 x ULN | 1.51 – 1.75 x ULN | > 1.75 x ULN | |
| Bilirubin – when liver function test is normal; increase by factor | 1.1 – 1.5 x ULN | 1.6 – 2.0 x ULN | 2.0 – 3.0 x ULN | > 3.0 x ULN | |
| Cholesterol | 201 – 210 | 211 – 225 | > 226 | --- | |
| Pancreatic enzymes – amylase, lipase | 1.1 – 1.5 x ULN | 1.6 – 2.0 x ULN | 2.1 – 5.0 x ULN | > 5.0 x ULN |
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory abnormalities as Potentially Life-Threatening (Grade 4). For example, a low sodium value that falls within a Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new seizure associated with the low sodium value.
***ULN is the upper limit of the normal range.
| Hematology * | Mild (Grade 1) | Moderate (Grade 2) | Severe (Grade 3) | Potentially Life-Threatening (Grade 4) | |
| Hemoglobin (female) - gm/dL | 11.0 – 12.0 | 9.5 – 10.9 | 8.0 – 9.4 | < 8.0 | |
| Hemoglobin (female) change from baseline value - gm/dL | Any decrease – 1.5 | 1.6 – 2.0 | 2.1 – 5.0 | > 5.0 | |
| Hemoglobin (male) - gm/dL | 12.5 – 13.5 | 10.5 – 12.4 | 8.5 – 10.4 | < 8.5 | |
| Hemoglobin (male) change from baseline value – gm/dL | Any decrease – 1.5 | 1.6 – 2.0 | 2.1 – 5.0 | > 5.0 | |
| WBC increase - cell/mm3 | 10,800 – 15,000 | 15,001 – 20,000 | 20,001 – 25, 000 | > 25,000 | |
| WBC decrease - cell/mm3 | 2,500 – 3,500 | 1,500 – 2,499 | 1,000 – 1,499 | < 1,000 | |
| Lymphocytes decrease - cell/mm3 | 750 – 1,000 | 500 – 749 | 250 – 499 | < 250 | |
| Neutrophils decrease - cell/mm3 | 1,500 – 2,000 | 1,000 – 1,499 | 500 – 999 | < 500 | |
| Eosinophils - cell/mm3 | 650 – 1500 | 1501 - 5000 | > 5000 | Hypereosinophilic | |
| Platelets decreased - cell/mm3 | 125,000 – 140,000 | 100,000 – 124,000 | 25,000 – 99,000 | < 25,000 | |
| PT – increase by factor (prothrombin time) | 1.0 – 1.10 x ULN** | 1.11 – 1.20 x ULN | 1.21 – 1.25 x ULN | > 1.25 ULN | |
| PTT – increase by factor (partial thromboplastin time) | 1.0 – 1.2 x ULN | 1.21 – 1.4 x ULN | 1.41 – 1.5 x ULN | > 1.5 x ULN | |
| Fibrinogen increase - mg/dL | 400 – 500 | 501 – 600 | > 600 | -- | |
| Fibrinogen decrease - mg/dL | 150 – 200 | 125 – 149 | 100 – 124 | < 100 or associated with gross bleeding or disseminated intravascular coagulation (DIC) |
| Urine * | Mild (Grade 1) | Moderate (Grade 2) | Severe (Grade 3) | Potentially Life-Threatening (Grade 4) | |
| Protein | Trace | 1+ | 2+ | Hospitalization or dialysis | |
| Glucose | Trace | 1+ | 2+ | Hospitalization for hyperglycemia | |
| Blood (microscopic) – red blood cells per high power field (rbc/hpf) | 1 – 10 | 11 – 50 | > 50 and/or gross blood | Hospitalization or packed red blood cells (PRBC) transfusion |
From: Guidance for industry: Toxicity Grading Scale for Healthy Adult and Adolescents Volunteers Enrolled in Preventive Vaccine Clinical Trials. https://www.fda.gov/media/73679/download