Table of Surrogate Endpoints

Acquired Hypofibrinogenemia Bleeding adults with acquired fibrinogenemia The total number of allogeneic blood product (ABP) units transfused in the first 24 hours after termination of cardiopulmonary bypass (CPB). Traditional Replacement for fibrinogen, a critical soluble plasma protein in the coagulation cascade, is provided Acromegaly Patients with acromegaly who don’t respond to or cannot undergo other standard therapies Serum Insulin-like growth factor-I (IGF-1) Traditional Growth hormone receptor antagonist Acromegaly Patients with acromegaly who don’t respond to or cannot undergo other standard therapies Serum growth hormone and serum insulin-like growth factor-I (IGF-1) Traditional Somatostatin analog Acute Bronchospasm Patients with acute bronchospasm associated with reversible obstructive airway disease or exercise Forced expiratory volume in 1 second (FEV1) Traditional Beta-2 adrenergic agonist Alzheimer’s disease Patients with mild cognitive impairment or mild dementia stage of Alzheimer’s disease Reduction in amyloid beta plaques Accelerated Monoclonal antibody Anthrax vaccine Persons at high risk of exposure to anthrax Anti-protective antigen antibody response Traditional Induction of immunity Anticoagulation reversal (needed due to life-threatening or uncontrolled bleeding) Patients treated with a direct or indirect FXa inhibitor when reversal of anticoagulation is needed Percent change in anti-FXa activity, from baseline to nadir Accelerated Binding and sequestering FXa inhibitors Asthma Patients with asthma Forced expiratory volume in 1 second (FEV1) Traditional Corticosteroid; Beta-2 adrenergic agonist Chronic kidney disease Patients with chronic kidney disease secondary to multiple etiologies Estimated glomerular filtration rate or serum creatinine Traditional Mechanism agnostic* Chronic obstructive pulmonary disease (COPD) Patients with COPD Forced expiratory volume in 1 second (FEV1) Traditional Corticosteroid; Long-acting beta2-adrenergic agonist; Anticholinergic; Phosphodiesterase 4 inhibitor COVID-19 and influenza Individuals 18 through 64 Years of Age Full-length S-binding IgG (for COVID-19) and Hemagglutination inhibition (HAI) antibodies (for influenza) Traditional Induction of antibodies against the S protein of SARS-CoV-2 and the hemagglutinin (HA) protein of influenza virus Cushing’s disease Patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative Urine free cortisol Traditional Somatostatin analog Cushing’s syndrome Patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery Urine free cortisol ˟ Traditional Cortisol synthesis inhibitor Cystic fibrosis Patients with cystic fibrosis Forced expiratory volume in 1 second (FEV1) Traditional Cystic fibrosis transmembrane conductance regulator potentiator Cystinuria Patients with cystinuria Urinary cystine Traditional Reducing and complexing thiol Cytomegalovirus (CMV) CMV seropositive and hematopoietic transplant recipients requiring prophylaxis Plasma CMV-DNA exceeding threshold for starting treatment 
   Traditional Antiviral Diphtheria vaccine (in combination vaccines) Persons to be immunized against diphtheria Anti-diphtheria toxoid antibody Traditional Induction of immunity Duchenne muscular dystrophy (DMD) Patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon skipping Skeletal muscle dystrophin Accelerated Antisense oligonucleotide Exocrine pancreatic insufficiency Patients with exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions Fecal coefficient of fat absorption Traditional Pancreatic enzymes that catalyze the hydrolysis of fats, proteins, and starches. Fabry disease Patients with confirmed Fabry disease Complete/near complete clearance of GL-3 inclusions in biopsied renal peritubular capillaries (using the Fabrazyme Scoring System) Traditional Enzyme replacement therapy Fabry disease Patients with confirmed Fabry disease and amenable GLA gene variants Reduction of GL-3 inclusions in biopsied renal peritubular capillaries (using the BLISS methodology) Accelerated Pharmacological chaperone Familial chylomicronemia syndrome Familial chylomicronemia syndrome percent change in fasting triglycerides from baseline Traditional APOC-III-directed antisense oligonucleotide (ASO) Female hypogonadotropic hypogonadism Infertile women with hypogonadotropic hypogonadism Follicle size, serum estradiol and progesterone# Traditional Gonadotropin First aid antiseptic; Health care antiseptic; Consumer antiseptic General public, consumers, and health care professionals Bacterial count Traditional and Monograph   Antimicrobial Gout Patients with gout Serum uric acid Traditional Xanthine oxidase inhibitor; URAT1 inhibitor; Uricase Hepatitis A (Hep A) vaccine Persons to be immunized against Hep A Anti-Hep A antigen antibody Traditional Induction of immunity Hepatitis B (Hep B) vaccine Persons to be immunized against Hep B Anti-Hep B antigen antibody Traditional Induction of immunity Hepatitis B Virus (all known subtypes) vaccine Adults > 18 yo to be immunized against all known suptypes of hepatitis b virus Neutralizing antibody >/= 10 mIU/mL Traditional Induction of antibodies to HBsAg. Hepatitis B Virus (HBV) Patients with HBV infection with or without cirrhosis Undetectable plasma HBV-DNA for indefinite treatment or HBsAg loss for finite treatment Traditional Antiviral Hepatitis C Virus (HCV) Patients with HCV infection with or without cirrhosis Sustained viral response (HCV-RNA) Traditional Antiviral Hepatitis D Virus (HDV) Patients with HDV infection with or without cirrhosis ≥ 2 log reduction in HDV-RNA plus normalization of ALT or HDV below the LLOQ˟ Accelerated Antiviral Hepatorenal syndrome Patients with hepatorenal syndrome type 1 Serum creatinine˟ Traditional Mechanism agnostic* Homozygous sitosterolemia (phytosterolemia) Patients with homozygous sitosterolemia (phytosterolemia) Plasma sitosterol and campesterol Traditional Dietary cholesterol absorption inhibitor Human Immunodeficiency Virus-1 (HIV-1) Patients with HIV-1 Undetectable plasma HIV RNA Traditional Antiviral Human Immunodeficiency Virus-1 (HIV-1) Patients at high risk of sexually acquired HIV-1 Serum HIV antibody Traditional Antiviral Human Immunodeficiency Virus-1 (HIV-1) Highly treatment-experienced HIV-1 patients Greater than 0.5 log reduction in plasma HIV RNA Traditional Antiviral Human Papillomavirus Persons (18 through 45 years of age) to be immunized against human papillomavirus Cervical intraepithelial neoplasia Traditional Induction of immunity Hypercholesterolemia Patients with heterozygous familial and nonfamilial hypercholesterolemia Serum LDL cholesterol Traditional Lipid-lowering Hypercholesterolemia Patients with homozygous familial hypercholesterolemia Serum LDL cholesterol Traditional Lipid-lowering Hyperkalemia Patients with hyperkalemia Serum potassium Traditional Potassium binder Hyperphosphatemia Dialysis patients with hyperphosphatemia Serum phosphate Traditional Phosphate binder Hypertension Patients with hypertension Blood pressure Traditional Mechanism agnostic* Hypertriglyceridemia Patients with severe hypertriglyceridemia Serum triglycerides Traditional Lipid-lowering Hypokalemia Patients with hypokalemia Serum potassium Traditional Potassium salts Hyponatremia Patients with hypervolemic and euvolemic hyponatremia Serum sodium Traditional Vasopressin receptor antagonist Hypotension Patients with distributive shock Blood pressure Traditional Alpha and beta adrenergic agonist; Vasopressin analog Hypothyroidism Patients with hypothyroidism Serum thyroid-stimulating hormone (TSH) Traditional Thyroid hormone analog Influenza A H5N1 vaccine Persons to be immunized against influenza Hemagglutination inhibition antibody Traditional Induction of Immunity Influenza vaccine Persons to be immunized against influenza Hemagglutination inhibition antibody Accelerated Induction of immunity Interoperative hemorrhage Patients who require reduction of blood pressure to reduce bleeding during surgery Blood pressure Traditional Vasodilator Invasive disease caused by Neisseria meningitidis Pateint (18-25 years old) with invasive disease caused by Neisseria meningitidis serogroups A, B, C, W, and Y Serum bactericidal activity (SBA) determined by endogenous complement preserved in the serum samples collected from study participants (enc hSBA) and SBA determined by an exogenous source of human complement (hSBA) Traditional Induction of Immunity Invasive disease caused by Streptococcus pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B; and pneumonia caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B. Persons to be immunized against S. pneumoniae 18 years of age and older Opsonophagocytic activity (OPA) Traditional Induction of Immunity Invasive pneumococcal disease Patients with invasive pneumococcal disease Opsonophagocytosis assay titers Traditional Induction of immunity Japanese encephalitis vaccine Persons to be immunized against Japanese encephalitis Neutralizing antibody Traditional Induction of immunity Lipodystrophy Patients with congenital or acquired generalized lipodystrophy Serum hemoglobin A1C, fasting glucose and triglycerides Traditional Leptin analog Lupus nephritis Patients with active lupus nephritis Complete renal response (CRR), defined as 1) a response in the urine proteinuria (protein-creatine ratio) and 2) preservation/improvement of renal function (estimated glomerular filtration rate) Traditional Immunosuppressant Lysosomal Acid Lipase (LAL) deficiency Patients with LAL deficiency Serum LDL-c levels Traditional Hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme Male hypogonadotropic hypogonadism with inferility Men with selected cases of hypogonadotropic hypogonadism with inferility Sperm parameters Traditional Gonadotropin Meningococcal (serogroups A, C, Y, W) meningitis vaccine Persons to be immunized against meningococcal meningitis Serum bactericidal antibody Traditional Induction of Immunity Meningococcal ACYW-135 vaccine Persons to be immunized against meningococcal meningitis Serum bactericidal antibody Traditional Induction of immunity Meningococcal Group B vaccine Persons (18 through 25 years of age) to be immunized against meningococcal meningitis Serum bactericidal antibody Traditional Induction of immunity Metabolic dysfunction associated steatohepatitis (MASH) Precirrhotic NASH patients with liver fibrosis Histopathologic findings of either 1) resolution of steatohepatitis with no worsening of fibrosis OR 2) improvement of fibrosis with no worsening of steatohepatitis OR 3) Both# Accelerated Anti-fibrotic; Anti-inflammatory Methylmalonic acidemia Patients with acute hyperammonemia due to methylmalonic acidemia Plasma ammonia Traditional Carbamoyl Phosphate Synthetase 1 activator Monkeypox vaccine Persons to be immunized against monkeypox Vaccinia-neutralizing antibody Traditional Induction of immunity Mycobacterium avium complex (MAC) lung disease Patients with MAC lung disease Sputum culture conversion to negative by six months Accelerated Antimicrobial N-acetylglutamate Synthase (NAGS) deficiency Patients with hyperammonemia due to NAGS deficiency Plasma ammonia Traditional Carbamoyl Phosphate Synthetase 1 activator Nonmalignant hematology Patients with Thrombocytopenia due to immune (idiopathic) thrombocytopenia or chronic hepatitis C Platelet count response Traditional Mechanism agnostic* Nonmalignant hematology Patients with chronic iron overload or non-transfusion-dependent thalassemia syndromes Serum ferritin and liver iron concentration Traditional Iron chelator Nonmalignant hematology Patients with anemia due to (1) chronic kidney disease, (2) chemotherapy-induced anemia, (3) zidoviduine in patients with HIV-infection Hematologic response and reduction in transfusion Traditional Mechanism agnostic* Nonmalignant hematology Patients with severe aplastic anemia Hematologic response Traditional Mechanism agnostic* Nonmalignant hematology Patients with methemoglobinemia Serum methemoglobin Accelerated Oxidation-reduction agent Nonmalignant hematology Patients in need of reversal of anticoagulant effects for emergency surgery/urgent procedures and in life-threatening or uncontrolled bleeding. Change in coagulation parameters Traditional Humanized monoclonal antibody fragment Nonmalignant hematology Patients with sickle cell disease Hemoglobin response rate Accelerated Hemoglobin S polymerization inhibitor Opioid use disorder Patients with opioid use disorder Urine toxicology test for opioids Traditional 1. Partial opioid agonist
2. Opioid antagonist Osteoporosis Postmenopausal women with osteoporosis New morphometric vertebral fractures Traditional Estrogen agonist/antagonist; Parathyroid hormone analog; Bisphosphonate; RANK ligand (RANKL) inhibitor Osteoporosis Patients with glucocorticoid induced osteoporosis Bone mineral density¤ Traditional Bisphosphonate; Parathyroid hormone analog; RANKL inhibitor Osteoporosis Men with osteoporosis Bone mineral density¤ Traditional Parathyroid hormone analog; Bisphosphonate; RANK ligand (RANKL) inhibitor Paget’s disease Patients with Paget’s disease Serum alkaline phosphatase Traditional Bisphosphonate Peri-implantitis Patients with peri-implantitis Probing pocket depth ˟ Traditional Antimicrobial Periodontitis Patients with chronic periodontitis with a mean probing pocket depth of greater than 5mm Probing pocket depth Traditional Antimicrobial Pertussis (in combination vaccines) Persons (18 through 64 years of age) to be immunized against pertussis Serum antibody concentrations Traditional Induction of immunity Phenylketonuria 1. Patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria
  2. Adults with PKU who have uncontrolled plasma Phe>600 micromol/L on existing management Plasma phenylalanine Traditional 1. Phenylalanine hydroxylase activator
2. Phenylalanine-metabolizing enzyme Pneumococcal conjugate vaccine Persons ( ≥ 50 years of age) to be immunized against pneumonia and invasive disease Opsonophagocytic antibody response Traditional/Accelerated Induction of immunity Polio vaccine Persons to be immunized against polio Neutralizing antibody response Traditional Induction of immunity Polycystic kidney disease Patients with autosomal dominant polycystic kidney disease with or without associated polycystic liver disease Total kidney volume ˟ Accelerated Mechanism agnostic* Preterm birth Women with a singleton pregnancy who have a history of singleton spontaneous preterm birth Delivery prior to 37 weeks gestation Accelerated Progesterone analog Primary biliary cholangitis Patients with primary biliary cholangitis Serum alkaline phosphatase and bilirubin# Accelerated Anti-fibrotic; Anti-inflammatory Primary glomerular diseases associated with significant proteinuria Patients with primary glomerular disease associated with significant proteinuria Proteinuria (urinary protein/creatinine ratio) Accelerated Mechanism agnostic* Primary hyperoxaluria type 1 (PH1) Patients with primary hyperoxaluria type 1 (PH1) Urinary oxalate Traditional siRNA against hyroxyacid oxidase 1 gene Primary hyperparathyroidism Patients with hypercalcemia due to primary hyperparathyroidism Serum calcium Traditional Calcium-sensing receptor agonist Propionic acidemia Patients with acute hyperammonemia due to propionc acidemia Plasma ammonia Traditional Carbamoyl Phosphate Synthetase 1 activator pulmonary disease Patients with congenital alpha-1 antitrypsin deficiency reduction in hepatic fibrosis Traditional Alpha-1 protease inhibitor augmentation Pulmonary fibrosis Patients with pulmonary fibrosis Forced vital capacity (FVC) Traditional Mechanism agnostic* Pulmonary tuberculosis Patients with active pulmonary tuberculosis Sputum culture conversion to negative Accelerated Antimicrobial Rabies immune globulin Patients with suspected exposure to a rabid animal Rabies neutralizing activity and antibody response Traditional Passive immunity Rabies Vaccine Persons to be immunized against rabies Neutralizing antibody Traditional Induction of immunity Respiratory Syncytial Virus, Lower Respiratory Tract Disease Pateints with Respiratory Syncytial Virus, Lower Respiratory Tract Disease Neutralizing antibodies to RSV A and B Traditional active immunization Secondary hyperparathyroidism associated with chronic kidney disease Patients with secondary hyperparathyroidism associated with chronic kidney disease Serum intact parathyroid hormone (iPTH) Traditional Calcium-sensing receptor agonist; Vitamin D3 analog Smallpox vaccine Persons to be immunized against smallpox Vaccinia-neutralizing antibody Traditional Induction of immunity Smallpox vaccine Persons to be immunized against smallpox Vaccination site take reaction (replicating smallpox vaccines only) Traditional Induction of immunity Supportive cancer care Patients with delayed methotrexate clearance due to impaired renal function Plasma methotrexate Traditional Carboxypeptidase Supportive cancer care Patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of uric acid Serum uric acid Traditional Uric acid specific enzyme Supportive cancer care Patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs Duration of severe neutropenia Traditional Leukocyte growth factor Supraventricular tachycardia adults with supraventricular tachycardia including atrial fibrillation and atrial flutter. Heart rate ** Traditional beta-1 adrenergic receptor antagonist Systemic sclerosis-interstitial lung disease Patents with systemic sclerosis-interstitial lung disease Forced vital capacity (FVC) Traditional Mechanism agnostic* Testosterone deficiency Men with primary or hypogonadotropic hypogonadism Serum testosterone Traditional Androgen, GnRH analog Tetanus vaccine Persons to be immunized against tetanus Anti-tetanus toxoid antibody Traditional Induction of immunity the prevention of disease caused by chikungunya virus (CHIKV) in individuals 18 years of age and older who are at increased risk of exposure to CHIKV 18 years of age and older who are at increased risk of exposure to CHIKV CHIKV-specific neutralizing antibody titer ≥150 as determined by micro-plaque reduction neutralization test (μPRNT50) Accelerated IXCHIQ elicits CHIKV-specific immune responses. The exact mechanism of protection has not been determined but protection is thought to be mediated by CHIKV-specific neutralizing antibodies. Tick-borne encephalitis vaccine Persons to be immunized against tick-borne encephalitis Neutralizing antibody Traditional Induction of immunity Tobacco dependence Cigarette smokers Exhaled carbon monoxide Traditional Smoking cessation Type 1 diabetes mellitus Patients with type 1 diabetes mellitus Serum hemoglobin A1C Traditional Glucose-lowering Type 1 Gaucher disease Patients with Type 1 Gaucher disease Spleen volume, liver volume, hemoglobin and platelet count# Traditional Glucosylceramide synthase inhibitor; Hydrolytic lysozomal glucocerebroside-specific enzyme Type 2 diabetes mellitus Patients with type 2 diabetes mellitus Serum hemoglobin A1C Traditional Glucose-lowering X-linked hypophosphatemia Patients with X-linked hypophosphatemia Serum phosphate Traditional Fibroblast growth factor 23 inhibitor Yellow fever vaccine Persons to be immunized against yellow fever Neutralizing antibody Traditional Induction of immunity

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