Blood samples collected were analyzed using the Somalogic SomaScan platform which provides a broad overview of proteomics changes by measuring approximately 7,000 proteins. It uses a highly multiplexed and high throughput aptamer-based proteomic technology and deoxyribonucleic acid (DNA)-microarray-based detection. It provides concentration domain values as relative fluorescence units (RFUs). Proteomics high-dimensional data was analyzed using a standard EN algorithm which utilizes a penalized regression method particularly adapted to the analysis of highly correlated data, as it eliminates redundant parameters while retaining interrelated parameters. Raw data obtained from each sample was entered into a classification model (iEN algorithm) that generated prediction values for proteomics which are presented in the data table. A prediction value of 1 and 2 indicated perfect results (i.e., positive response to treatment) for the GRF6021 and the placebo group, respectively.

The 3D-CAM is a brief verbal assessment tool used to test participants for delirium. Each item in the instrument directly informs one of the 4 CAM features including acute onset of mental status change or fluctuating course of cognition, inattention, disorganized thinking, and altered level of consciousness. For all items on the assessment, the participants answered as "incorrect," "correct," "no," or "yes". The CAM algorithm is considered positive if the following features are present: Feature 1) Acute onset or fluctuating course and Feature 2) Inattention and either Feature 3) Disorganized thinking or Feature 4) Altered level of consciousness. Number of participants at baseline and postbaseline with delirium "present" or "not present" are reported here. The baseline was defined as Day 1 pre-infusion measurement.

SRS is sensitive & simple tool for assessment of functional recovery following major surgery & consist of 13 items. Impacts on daily activities are scored from 1 (not at all) to 5/6 (all the time). First 8 items were scored from 1 to 6. Rest were scored from 1 to 5. SRS scores were obtained by reversing responses (e.g., 1=6, 2=5, 3=4, 4=3, 5=2 and 6=1) to 5 negatively stated items (items 2, 4, 5, 6, and 7) & then summing across all scale items for an individual at baseline & each scheduled post-baseline time point. SRS total score range=13-63 where higher score indicated better recovery. For postoperative visits 'not applicable' responses were coded into same category as affirmations of 'not at all'. For all other time points 'not applicable' responses were coded as missing data. KM estimate of survival was to be used to summarize time (in Days) from date of randomization to 50% recovery of baseline value in SRS by treatment group. Baseline = Day -7 to -3 pre-infusion measurement.

WOMAC is a widely utilized self-report measure of lower extremity symptoms and function. The WOMAC Likert Scale version used an 11-point scale anchored by the wording "no pain" and "extreme pain" for pain, and "no difficulty" and "extreme difficulty" for physical function. There were 5 questions for pain and 17 questions for physical function (total 22 questions). Scores (maximum 10) for each question of WOMAC were summed for an individual at the End of Study. The calculated scores were used to summarize the WOMAC score by treatment group. For this outcome measure, a full WOMAC score 0-220 point scale was used for data analysis. Higher scores on the WOMAC indicate worse pain and physical functional limitations.

WOMAC is a widely utilized self-report measure of lower extremity symptoms and function. The WOMAC Likert Scale version uses an 11-point scale anchored by the wording "no pain" (score=0) and "extreme pain" (score=10) for the pain subscale. The pain subscale consists of 4 items. The total score ranges from 0 (best) to 40 (worse). Higher scores on the WOMAC indicate worse pain. Kaplan Meier (KM) estimate of survival was used to summarize the time (in Days) from the date of randomization to the day when the participant had a non-missing score of < 12. Right-censoring was used to produce Kaplan-Meier time-to-event estimates.

WOMAC is a widely utilized self-report measures of lower extremity symptoms and function. WOMAC Likert Scale version uses an 11-point scale anchored by the wording "no difficulty" (score=0) and "extreme difficulty" (score=10) for physical function subscale. The physical function subscale consists of 6 items. The total score ranges from 0 (best) to 60 (worse). Higher scores on the WOMAC indicate more functional limitations. Kaplan Meier (KM) estimate of survival was used to summarize the time (in Days) from the date of randomization to the day when participant had a non-missing score of < 18. Right-censoring was used to produce Kaplan-Meier time-to-event estimates.

The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. The MCS ranges from 0 (worst) to 100 (best), and higher score indicates better mental health status. Positive change from baseline indicates improvement. The baseline was defined as Day -7 to -3 prior to surgery.

The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 primarily contribute to the Physical Component Summary (PCS) score of the SF-36. The PCS ranges from 0 (worst) to 100 (best), and a higher score indicates better physical condition. Positive change from baseline indicates improvement. The baseline was defined as Day -7 to -3 prior to surgery.

The BDI-II is a 21-item questionnaire used to assess depression. Most items are rated on a 4-point scale from 0 to 3, and a few items are rated on a 7-point scale. Individual item scores are added to get a total BDI-II score from 0 to 63. The higher the total score, the more severe the depression, and the lower the total score, the less severe the depression. A negative change from baseline indicated an improvement. The baseline was defined as Day -7 to -3 prior to surgery.

The Kaplan-Meier (KM) estimate of survival was used to summarize the time (in Days) from the date of randomization to discharge from the hospital by treatment group using median and inter quartile ranges: Q1 (25th percentile) and Q3 (75th percentile).

The duration (in hours) for which a participant underwent surgery i.e., primary hip or knee arthroplasty is reported here.

The duration (in hours) for which a participant was under anesthesia is reported here.

The duration (in hours) for which the participants stayed at the PACU is reported here.

ASA class ranges from ASA I - ASA VI. Higher ASA class with other factors (surgery type, frailty, and deconditioning) help predict greater perioperative risk. Normal healthy participants are categorized under ASA I, whereas participants with mild systematic disease and severe systematic disease are graded as ASA II and ASA III, respectively. If participants have severe systematic disease that is a constant threat to their life, they are graded as ASA IV. A moribund participant who is not expected to survive without the operation is classified as ASA V. ASA VI includes participants that are declared brain-dead and whose organs are being removed for donor purposes.

Intraoperative fluids administered were summarized by WHO Drug Dictionary (WHO-DD) Version 2018 Anatomical Therapeutic Chemical (ATC) level 3 terms and standardized medication names.

Intraoperative blood products administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names.

Intraoperative anesthesia administered were summarized using WHO-DD Version 2018 ATC level 3 terms and standardized medication names.

The number of participants with intraoperative opioids administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names.

Participants with abnormal chemistry values as assessed by the investigator are reported here. The marked reference range are as follows: calcium <1.12 or > 1.47 millimoles per liter (mmol/L) and sodium < 130 or > 150 mmol/L.

Participants with abnormal hematology values as assessed by the investigator are reported here. Hematology abnormalities were only observed on Day 3. The marked reference range are as follows: hematocrit < 30 or > 58%, hemoglobin < 10 or > 20 grams per deciliter (g/dL) and Lymphocytes/Leukocytes < 10 or > 60%.

Participants with abnormal coagulation values as assessed by the investigator are reported here. The marked reference range are as follows: prothrombin international normalized ratio > 1.3, prothrombin time > 20 seconds, and activated partial thromboplastin time > 45 seconds.

Participants with abnormal urinalysis values as assessed by the investigator are reported here. The normalized estimated glomerular filtration rate (eGFR) values were (mL/min/surface area (SA)) < 55.

Participants with abnormal blood pressure measurements as assessed by the investigator are reported here. The following parameters were considered in the assessment of abnormal blood pressure measurements: systolic blood pressure >180 millimeters of mercury (mmHg); systolic blood pressure > 200 mmHg; diastolic blood pressure < 50 mmHg.

A 12-lead ECG was to be performed to obtain heart rate. The baseline was defined as Day 1 pre-infusion measurement.

A 12-lead ECG was performed after the participant had rested quietly for at least 5 minutes in a supine or sitting position. The parameters evaluated from the participant ECG trace included QT interval and QTc (corrected). Corrected QTc intervals were calculated using Fridericia's correction formula. The baseline was defined as Day 1 pre-infusion measurement.

Participants received 4 doses of GRF6021 matching placebo, 250 mL, IV infusion. The first dose was administered on day before surgery, the next two doses on the day of surgery i.e., within 4 hours before start of surgery (first incision), and then upon arrival in the postoperative care unit (within 5 hours after the first incision) and the last dose was administered on the day after the surgery.

Total of all reporting groups

At screening, participants were provided with an ActiGraph wearable device & approximately -7 to -3 days before surgery, they were instructed to wear the device. ActiGraph wearable device was used to monitor participants' physical activity, mobility & sleep. Functional status including heart rate & sleep time were collected during the study period except perioperative times when it was removed for surgery. ActiGraph high-dimensional data was analyzed using a standard EN algorithm which utilizes a penalized regression method particularly adapted to the analysis of highly correlated data, as it eliminates redundant parameters while retaining interrelated parameters. Raw data obtained over the entire observation period was entered into a classification model (iEN algorithm) that generated prediction values (presented below) for functional status changes. A prediction value of 1 &2 indicated perfect results (i.e., positive response to treatment) for GRF6021 & placebo groups, respectively.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected. Overall number of participants analyzed is the number of participants available for analysis.

Blood samples collected were analyzed using the Somalogic SomaScan platform which provides a broad overview of proteomics changes by measuring approximately 7,000 proteins. It uses a highly multiplexed and high throughput aptamer-based proteomic technology and deoxyribonucleic acid (DNA)-microarray-based detection. It provides concentration domain values as relative fluorescence units (RFUs). Proteomics high-dimensional data was analyzed using a standard EN algorithm which utilizes a penalized regression method particularly adapted to the analysis of highly correlated data, as it eliminates redundant parameters while retaining interrelated parameters. Raw data obtained from each sample was entered into a classification model (iEN algorithm) that generated prediction values for proteomics which are presented in the data table. A prediction value of 1 and 2 indicated perfect results (i.e., positive response to treatment) for the GRF6021 and the placebo group, respectively.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected. Overall number of participants analyzed is the number of participants available for analysis.

The 3D-CAM is a brief verbal assessment tool used to test participants for delirium. Each item in the instrument directly informs one of the 4 CAM features including acute onset of mental status change or fluctuating course of cognition, inattention, disorganized thinking, and altered level of consciousness. For all items on the assessment, the participants answered as "incorrect," "correct," "no," or "yes". The CAM algorithm is considered positive if the following features are present: Feature 1) Acute onset or fluctuating course and Feature 2) Inattention and either Feature 3) Disorganized thinking or Feature 4) Altered level of consciousness. Number of participants at baseline and postbaseline with delirium "present" or "not present" are reported here. The baseline was defined as Day 1 pre-infusion measurement.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

SRS is sensitive & simple tool for assessment of functional recovery following major surgery & consist of 13 items. Impacts on daily activities are scored from 1 (not at all) to 5/6 (all the time). First 8 items were scored from 1 to 6. Rest were scored from 1 to 5. SRS scores were obtained by reversing responses (e.g., 1=6, 2=5, 3=4, 4=3, 5=2 and 6=1) to 5 negatively stated items (items 2, 4, 5, 6, and 7) & then summing across all scale items for an individual at baseline & each scheduled post-baseline time point. SRS total score range=13-63 where higher score indicated better recovery. For postoperative visits 'not applicable' responses were coded into same category as affirmations of 'not at all'. For all other time points 'not applicable' responses were coded as missing data. KM estimate of survival was to be used to summarize time (in Days) from date of randomization to 50% recovery of baseline value in SRS by treatment group. Baseline = Day -7 to -3 pre-infusion measurement.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

WOMAC is a widely utilized self-report measure of lower extremity symptoms and function. The WOMAC Likert Scale version used an 11-point scale anchored by the wording "no pain" and "extreme pain" for pain, and "no difficulty" and "extreme difficulty" for physical function. There were 5 questions for pain and 17 questions for physical function (total 22 questions). Scores (maximum 10) for each question of WOMAC were summed for an individual at the End of Study. The calculated scores were used to summarize the WOMAC score by treatment group. For this outcome measure, a full WOMAC score 0-220 point scale was used for data analysis. Higher scores on the WOMAC indicate worse pain and physical functional limitations.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected. Overall number analyzed is the number of participants with data available for analysis.

WOMAC is a widely utilized self-report measure of lower extremity symptoms and function. The WOMAC Likert Scale version uses an 11-point scale anchored by the wording "no pain" (score=0) and "extreme pain" (score=10) for the pain subscale. The pain subscale consists of 4 items. The total score ranges from 0 (best) to 40 (worse). Higher scores on the WOMAC indicate worse pain. Kaplan Meier (KM) estimate of survival was used to summarize the time (in Days) from the date of randomization to the day when the participant had a non-missing score of < 12. Right-censoring was used to produce Kaplan-Meier time-to-event estimates.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

WOMAC is a widely utilized self-report measures of lower extremity symptoms and function. WOMAC Likert Scale version uses an 11-point scale anchored by the wording "no difficulty" (score=0) and "extreme difficulty" (score=10) for physical function subscale. The physical function subscale consists of 6 items. The total score ranges from 0 (best) to 60 (worse). Higher scores on the WOMAC indicate more functional limitations. Kaplan Meier (KM) estimate of survival was used to summarize the time (in Days) from the date of randomization to the day when participant had a non-missing score of < 18. Right-censoring was used to produce Kaplan-Meier time-to-event estimates.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. The MCS ranges from 0 (worst) to 100 (best), and higher score indicates better mental health status. Positive change from baseline indicates improvement. The baseline was defined as Day -7 to -3 prior to surgery.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 primarily contribute to the Physical Component Summary (PCS) score of the SF-36. The PCS ranges from 0 (worst) to 100 (best), and a higher score indicates better physical condition. Positive change from baseline indicates improvement. The baseline was defined as Day -7 to -3 prior to surgery.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The BDI-II is a 21-item questionnaire used to assess depression. Most items are rated on a 4-point scale from 0 to 3, and a few items are rated on a 7-point scale. Individual item scores are added to get a total BDI-II score from 0 to 63. The higher the total score, the more severe the depression, and the lower the total score, the less severe the depression. A negative change from baseline indicated an improvement. The baseline was defined as Day -7 to -3 prior to surgery.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected. Overall number analyzed is the number of participants with data available for analysis.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The Kaplan-Meier (KM) estimate of survival was used to summarize the time (in Days) from the date of randomization to discharge from the hospital by treatment group using median and inter quartile ranges: Q1 (25th percentile) and Q3 (75th percentile).

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The duration (in hours) for which a participant underwent surgery i.e., primary hip or knee arthroplasty is reported here.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The duration (in hours) for which a participant was under anesthesia is reported here.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The duration (in hours) for which the participants stayed at the PACU is reported here.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

ASA class ranges from ASA I - ASA VI. Higher ASA class with other factors (surgery type, frailty, and deconditioning) help predict greater perioperative risk. Normal healthy participants are categorized under ASA I, whereas participants with mild systematic disease and severe systematic disease are graded as ASA II and ASA III, respectively. If participants have severe systematic disease that is a constant threat to their life, they are graded as ASA IV. A moribund participant who is not expected to survive without the operation is classified as ASA V. ASA VI includes participants that are declared brain-dead and whose organs are being removed for donor purposes.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

Intraoperative fluids administered were summarized by WHO Drug Dictionary (WHO-DD) Version 2018 Anatomical Therapeutic Chemical (ATC) level 3 terms and standardized medication names.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

Intraoperative blood products administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

Intraoperative anesthesia administered were summarized using WHO-DD Version 2018 ATC level 3 terms and standardized medication names.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

The number of participants with intraoperative opioids administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.

Participants with abnormal chemistry values as assessed by the investigator are reported here. The marked reference range are as follows: calcium <1.12 or > 1.47 millimoles per liter (mmol/L) and sodium < 130 or > 150 mmol/L.

Safety population consisted of all participants who received at least 1 dose of the study treatment.

Participants with abnormal hematology values as assessed by the investigator are reported here. Hematology abnormalities were only observed on Day 3. The marked reference range are as follows: hematocrit < 30 or > 58%, hemoglobin < 10 or > 20 grams per deciliter (g/dL) and Lymphocytes/Leukocytes < 10 or > 60%.

Safety population consisted of all participants who received at least 1 dose of the study treatment.

Participants with abnormal coagulation values as assessed by the investigator are reported here. The marked reference range are as follows: prothrombin international normalized ratio > 1.3, prothrombin time > 20 seconds, and activated partial thromboplastin time > 45 seconds.

Safety population consisted of all participants who received at least 1 dose of the study treatment.

Participants with abnormal urinalysis values as assessed by the investigator are reported here. The normalized estimated glomerular filtration rate (eGFR) values were (mL/min/surface area (SA)) < 55.

Safety population consisted of all participants who received at least 1 dose of the study treatment.

Participants with abnormal blood pressure measurements as assessed by the investigator are reported here. The following parameters were considered in the assessment of abnormal blood pressure measurements: systolic blood pressure >180 millimeters of mercury (mmHg); systolic blood pressure > 200 mmHg; diastolic blood pressure < 50 mmHg.

Safety population included all participants who received at least 1 dose of the study treatment.

A 12-lead ECG was to be performed to obtain heart rate. The baseline was defined as Day 1 pre-infusion measurement.

Safety population included all participants who received at least 1 dose of the study treatment. Number analyzed is the number of participants available for analysis at the specified time points.

A 12-lead ECG was performed after the participant had rested quietly for at least 5 minutes in a supine or sitting position. The parameters evaluated from the participant ECG trace included QT interval and QTc (corrected). Corrected QTc intervals were calculated using Fridericia's correction formula. The baseline was defined as Day 1 pre-infusion measurement.

Safety population included all participants who received at least 1 dose of the study treatment. Number analyzed is the number of participants available for analysis at the specified time points.

CyTOF=multiplexed, high-content immune profiling technology, providing high-resolution surveillance of circulating immune cells & response to GRF6021 infusions on surgical recovery. Blood samples were collected for CyTOF analysis & were stimulated with a series of extracellular ligands to analyze evoked intracellular signaling responses. High-dimensional data results were obtained from CytOF, and analyzed using the immunological elastic net (iEN) algorithm, a penalized regression method particularly adapted for the analysis of highly correlated data, as it eliminates redundant parameters while retaining interrelated parameters. Raw data obtained from each sample was entered into the classification model (iEN algorithm) that generated prediction values (presented below) showing the effect of study treatment on immune response post-surgery. A prediction value of 0 & 1 indicated perfect results (i.e., positive response to treatment) for the placebo & GRF6021 arms, respectively.

Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected. Overall number of participants analyzed is the number of participants available for analysis.

Participants received 4 doses of GRF6021 matching placebo, 250 mL, IV infusion. The first dose was administered on day before surgery, the next two doses on the day of surgery i.e., within 4 hours before start of surgery (first incision), and then upon arrival in the postoperative care unit (within 5 hours after the first incision) and the last dose was administered on the day after the surgery.