Trial Outcomes & Findings for A Study to Evaluate the Effect of GRF6021 on Postoperative Recovery Following Primary Hip or Knee Arthroplasty (NCT NCT03981419)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

38 participants

Primary outcome timeframe

Day 2 (before start of surgery and post surgery)

Results posted on

2024-03-13

Participant Flow

Participants took part in this study at one investigative site in the United States from 12 July 2019 to 04 March 2021.

Participants who were scheduled to undergo primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) were randomized in 1:1 ratio to receive GRF6021 or placebo. A total of 55 participants were screened, out of which 38 participants were enrolled in the study.

Participant milestones

Participant milestones
Measure	GRF6021 Participants received 4 doses of GRF6021, 250 milliliters (mL), intravenous (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.	Placebo 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.
Overall Study STARTED	18	20
Overall Study Intent-to-Treat (ITT) Population	18	20
Overall Study Safety Population	18	20
Overall Study Evaluable Population	18	19
Overall Study COMPLETED	18	19
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	GRF6021 Participants received 4 doses of GRF6021, 250 milliliters (mL), intravenous (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.	Placebo 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.
Overall Study Due to Coronavirus Disease-2019 (COVID-19)	0	1

Baseline Characteristics

A Study to Evaluate the Effect of GRF6021 on Postoperative Recovery Following Primary Hip or Knee Arthroplasty

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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 n=38 Participants Total of all reporting groups
Age, Continuous	70.70 years STANDARD_DEVIATION 5.86 • n=5 Participants	65.40 years STANDARD_DEVIATION 8.39 • n=7 Participants	67.89 years STANDARD_DEVIATION 7.70 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	17 Participants n=5 Participants	20 Participants n=7 Participants	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized White	8 Participants n=5 Participants	16 Participants n=7 Participants	24 Participants n=5 Participants
Race/Ethnicity, Customized Not Reported	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Other	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 2 (before start of surgery and post surgery)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=18 Participants 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.
Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 2 Day 2 (Before Surgery Start)	0.5692 predicted value Interval 0.4559 to 0.6269	0.4521 predicted value Interval 0.3935 to 0.5975
Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 2 Day 2 (Post Surgery)	0.5326 predicted value Interval 0.518 to 0.551	0.4471 predicted value Interval 0.431 to 0.4853

PRIMARY outcome

Timeframe: Day 3

Population: 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.

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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=18 Participants 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.
Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 3	0.7829 predicted value Interval 0.5941 to 0.8824	0.2871 predicted value Interval 0.1201 to 0.709

SECONDARY outcome

Timeframe: Baseline; Day 1, Day 3 up to approximately Day 46

Population: 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.

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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=18 Participants 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.
Change in Functional Status Using the ActiGraph Wearable Device Providing Measurements for Physical Activity/Function and Sleep	1.7007 predicted value Interval 1.6314 to 1.72	1.3861 predicted value Interval 1.3289 to 1.5009

SECONDARY outcome

Timeframe: Pre-infusion on Day 1 (baseline), 2 (before start of surgery and post surgery), and Day 3

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=18 Participants 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.
Effects of GRF6021 on Plasma Proteomics Day 1 (Baseline)	1.4320 predicted value Interval 1.2641 to 1.6601	1.3716 predicted value Interval 1.2417 to 1.7486
Effects of GRF6021 on Plasma Proteomics Day 2 (Before Surgery Start)	1.4189 predicted value Interval 1.2135 to 1.7029	1.5245 predicted value Interval 1.3442 to 1.6457
Effects of GRF6021 on Plasma Proteomics Day 2 (Post Surgery)	1.1563 predicted value Interval 1.0322 to 1.4885	1.7264 predicted value Interval 1.4567 to 1.9209
Effects of GRF6021 on Plasma Proteomics Day 3	1.3971 predicted value Interval 1.1933 to 1.5818	1.6284 predicted value Interval 1.4737 to 1.9543

SECONDARY outcome

Timeframe: Baseline (Day 1 pre-infusion); Days 2 (post-infusion), and 3 (pre-infusion)

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

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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Number of Participants With Change From Baseline in Delirium as Assessed Using 3-Minute Diagnostic Interview for Confusion Assessment Method (3-Minute Diagnostic Interview for Confusion [3D-CAM]) Baseline: Delirium Present	0 Participants	0 Participants
Number of Participants With Change From Baseline in Delirium as Assessed Using 3-Minute Diagnostic Interview for Confusion Assessment Method (3-Minute Diagnostic Interview for Confusion [3D-CAM]) Baseline: Delirium Not Present	18 Participants	19 Participants
Number of Participants With Change From Baseline in Delirium as Assessed Using 3-Minute Diagnostic Interview for Confusion Assessment Method (3-Minute Diagnostic Interview for Confusion [3D-CAM]) Change from Baseline at Day 2: Delirium Present	2 Participants	0 Participants
Number of Participants With Change From Baseline in Delirium as Assessed Using 3-Minute Diagnostic Interview for Confusion Assessment Method (3-Minute Diagnostic Interview for Confusion [3D-CAM]) Change from Baseline at Day 2: Delirium Not Present	16 Participants	19 Participants
Number of Participants With Change From Baseline in Delirium as Assessed Using 3-Minute Diagnostic Interview for Confusion Assessment Method (3-Minute Diagnostic Interview for Confusion [3D-CAM]) Change from Baseline at Day 3: Delirium Present	0 Participants	0 Participants
Number of Participants With Change From Baseline in Delirium as Assessed Using 3-Minute Diagnostic Interview for Confusion Assessment Method (3-Minute Diagnostic Interview for Confusion [3D-CAM]) Change from Baseline at Day 3: Delirium Not Present	18 Participants	19 Participants

SECONDARY outcome

Timeframe: Baseline; Days 1 and 3 (pre-infusion) and thereafter up to the end of the study (approximately Day 46)

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Time to 50% Recovery of Baseline Value on the Surgery Recovery Scale (SRS)	11.5 days Interval 8.0 to 15.0	15.0 days Interval 8.0 to 24.0

SECONDARY outcome

Timeframe: At end of study (approximately Day 46)

Population: 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 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=17 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
End of Study (EOS) Treatment Comparison of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)	28.50 score on a scale Standard Deviation 27.39	37.30 score on a scale Standard Deviation 38.80

SECONDARY outcome

Timeframe: Days 1 and 3 (pre-infusion) and thereafter up to Day 39

Population: 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 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Time to a Score of < 12/40 on a Subset of Questions From the WOMAC, Pain Subscale	13.5 days Interval 8.0 to 22.0	16.0 days Interval 5.0 to 29.0

SECONDARY outcome

Timeframe: Days 1 and 3 (pre-infusion) and thereafter up to Day 39

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Time to a Score of < 18/60 on a Subset of Questions From the WOMAC, Physical Function Subscale	18.0 days Interval 11.0 to 22.0	18.0 days Interval 11.0 to 36.0

SECONDARY outcome

Timeframe: At Baseline and end of study (approximately Day 46)

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Change From Baseline in Mental Health Score in the Short Form-36 (SF-36) Baseline	56.7 score on a scale Standard Deviation 10.16	57.6 score on a scale Standard Deviation 8.50
Change From Baseline in Mental Health Score in the Short Form-36 (SF-36) Change From Baseline at End of Study	2.1 score on a scale Standard Deviation 7.13	0.8 score on a scale Standard Deviation 8.62

SECONDARY outcome

Timeframe: At Baseline and end of study (approximately Day 46)

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Change From Baseline in Physical Health Score in the SF-36 Baseline	32.7 score on a scale Standard Deviation 6.87	34.9 score on a scale Standard Deviation 9.68
Change From Baseline in Physical Health Score in the SF-36 Change From Baseline at End of Study	4.0 score on a scale Standard Deviation 7.92	3.3 score on a scale Standard Deviation 9.90

SECONDARY outcome

Timeframe: At Baseline and end of study (approximately Day 46)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=18 Participants 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.
Change From Baseline in the Beck Depression Inventory-II (BDI-II) Baseline	7.3 score on a scale Standard Deviation 9.47	5.1 score on a scale Standard Deviation 5.47
Change From Baseline in the Beck Depression Inventory-II (BDI-II) Change From Baseline at End of Study	-3.2 score on a scale Standard Deviation 9.28	-2.7 score on a scale Standard Deviation 5.65

SECONDARY outcome

Timeframe: From Day 2 (post-surgery) up to end of study (approximately Day 46)

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

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Number of Participants With Opioid Analgesic Consumption During Hospital Stay and After Discharge to End of Study	18 Participants	19 Participants

SECONDARY outcome

Timeframe: Day 1 up to end of study (approximately Day 46)

Population: 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).

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Time to Discharge	2.0 days Interval 2.0 to 2.0	2.0 days Interval 2.0 to 2.0

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Perioperative Outcome: Surgery Duration	1.8 hours Interval 1.1 to 2.4	1.6 hours Interval 1.3 to 2.1

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Perioperative Outcome: Duration for Which Participants Were Under Anesthesia	3.0 hours Interval 2.3 to 4.6	2.7 hours Interval 2.3 to 4.6

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Perioperative Outcome: Duration of Stay in the Post-Anesthesia Care Unit (PACU)	2.6 hours Interval 1.6 to 5.3	2.9 hours Interval 1.5 to 8.0

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class ASA I	0 Participants	0 Participants
Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class ASA Il	8 Participants	12 Participants
Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class ASA III	10 Participants	7 Participants
Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class ASA IV	0 Participants	0 Participants
Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class ASA V	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 2

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

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Perioperative Outcome: Estimated Blood Loss	113.6 mL Standard Deviation 60.00	135.8 mL Standard Deviation 96.63

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Number of Participants in Whom Intraoperative Fluids Were Administered	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Number of Participants in Whom Intraoperative Blood Products Were Administered	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Number of Participants Who Received Intraoperative Anesthesia General Anesthesia	18 Participants	19 Participants
Number of Participants Who Received Intraoperative Anesthesia Local Anesthesia	15 Participants	19 Participants

SECONDARY outcome

Timeframe: Day 2

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=19 Participants 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.
Number of Participants Who Received Intraoperative Opioids Oxycodone	17 Participants	19 Participants
Number of Participants Who Received Intraoperative Opioids Hydromorphone	9 Participants	6 Participants
Number of Participants Who Received Intraoperative Opioids Tramadol	2 Participants	3 Participants
Number of Participants Who Received Intraoperative Opioids Oxycodone hydrochloride	1 Participants	2 Participants
Number of Participants Who Received Intraoperative Opioids Hydrocodone	2 Participants	3 Participants
Number of Participants Who Received Intraoperative Opioids Codeine	1 Participants	0 Participants
Number of Participants Who Received Intraoperative Opioids Hydromorphone hydrochloride	0 Participants	1 Participants
Number of Participants Who Received Intraoperative Opioids Tramadol hydrochloride	0 Participants	1 Participants

SECONDARY outcome

Timeframe: At Screening and Day 3

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

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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Number of Participants With Abnormal Laboratory Blood Chemistry Values Screening: Calcium, Ionized (mmol/L): High > 1.47	1 Participants	0 Participants
Number of Participants With Abnormal Laboratory Blood Chemistry Values Day 3: Calcium, Ionized (mmol/L): Low < 1.12	0 Participants	1 Participants
Number of Participants With Abnormal Laboratory Blood Chemistry Values Day 3: Sodium (mmol/L): Low < 130	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Day 3

Population: 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%.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Number of Participants With Abnormal Laboratory Hematology Values Day 3: Hematocrit (%): Low < 30	6 Participants	1 Participants
Number of Participants With Abnormal Laboratory Hematology Values Day 3: Hemoglobin (g/dL): Low < 10	8 Participants	4 Participants
Number of Participants With Abnormal Laboratory Hematology Values Day 3: Lymphocytes/Leukocytes (%): Low < 10	3 Participants	3 Participants

SECONDARY outcome

Timeframe: At Screening and Day 3

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Number of Participants With Abnormal Laboratory Coagulation Values At Screening: Prothrombin International Normalized Ratio: High > 1.3	1 Participants	1 Participants
Number of Participants With Abnormal Laboratory Coagulation Values At Screening: Prothrombin Time (seconds): High > 20	1 Participants	0 Participants
Number of Participants With Abnormal Laboratory Coagulation Values Day 3: Activated Partial Thromboplastin Time (seconds): High > 45	0 Participants	2 Participants
Number of Participants With Abnormal Laboratory Coagulation Values Day 3: Prothrombin International Normalized Ratio: High > 1.3	4 Participants	3 Participants
Number of Participants With Abnormal Laboratory Coagulation Values Day 3: Prothrombin Time (seconds): High > 20	2 Participants	3 Participants

SECONDARY outcome

Timeframe: At Screening and Day 3

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Number of Participants With Abnormal Laboratory Urinalysis Values	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Pre-infusion at Days 1, 2 (Pre and Postoperative) and 3; At Post infusion on Day 1 (15, 30, 45, 60 mins); Day 2 Preoperative (15, 30, 45 mins); Postoperative (30 mins); Day 3 (15 and 30 mins); and 30 mins after end of each infusion

Population: Safety population included 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (45 Minutes Post Infusion)	2 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 200 mmHg: On Day 2 Preoperative (30 Minutes Post Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 3 (30 Minutes After End of Infusion)	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 1 (Prior to Infusion)	1 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 1 (30 Minutes After End of Infusion)	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (Prior to Infusion)	1 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (15 Minutes Post Infusion)	1 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (30 Minutes Post Infusion)	1 Participants	2 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 180 mmHg: On Day 2 Postoperative (Prior to Infusion)	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Systolic Blood Pressure > 200 mmHg: On Day 2 Preoperative (15 Minutes Post Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 1 (Prior to Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 1 (15 Minutes Post Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 1 (30 Minutes Post Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 1 (45 Minutes Post Infusion)	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 1 (60 Minutes Post Infusion)	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 1 (30 Minutes After End of Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 2 Preoperative (30 Minutes After End of Infusion)	1 Participants	2 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 2 Postoperative (30 Minutes Post Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 3 (Prior to Infusion)	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 3 (15 Minutes Post Infusion)	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements Diastolic Blood Pressure < 50 mmHg: On Day 3 (30 Minutes Post Infusion)	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1 pre-infusion); Day 3 pre and post-infusion

Population: 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 to be performed to obtain heart rate. The baseline was defined as Day 1 pre-infusion measurement.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate At Baseline	63.7 beats/minute Standard Deviation 7.05	64.5 beats/minute Standard Deviation 11.24
Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate Change From Baseline on Day 3 (Prior to Infusion)	1.2 beats/minute Standard Deviation 9.16	5.1 beats/minute Standard Deviation 11.08
Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate Change From Baseline on Day 3 (Post Infusion)	8.4 beats/minute Standard Deviation 7.73	5.7 beats/minute Standard Deviation 11.96

SECONDARY outcome

Timeframe: Baseline (Day 1 pre-infusion); Day 3 pre and post-infusion

Population: 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.

Outcome measures

Outcome measures
Measure	GRF6021 n=18 Participants Participants received 4 doses of GRF6021, 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.	Placebo n=20 Participants 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.
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) QT Interval: At Baseline	422.1 msec Standard Deviation 31.13	408.9 msec Standard Deviation 26.02
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) QT Interval: Change From Baseline on Day 3 (Prior to Infusion)	2.6 msec Standard Deviation 36.64	-9.3 msec Standard Deviation 37.04
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) QT Interval: Change From Baseline on Day 3 (Post Infusion)	-24.3 msec Standard Deviation 22.52	-15.6 msec Standard Deviation 31.01
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) QTcF: At Baseline	429.1 msec Standard Deviation 22.38	416.4 msec Standard Deviation 16.68
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) QTcF: Change From Baseline on Day 3 (Prior to Infusion)	6.4 msec Standard Deviation 22.48	-1.3 msec Standard Deviation 23.71
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) QTcF: Change From Baseline on Day 3 (Post Infusion)	-7.3 msec Standard Deviation 15.08	-4.1 msec Standard Deviation 14.91

Adverse Events

GRF6021

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Head of Communications

Alkahest, Inc.

Phone: (650) 801-0474

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement contains language that restricts the PI from discussing or publishing Sponsor confidential and/or proprietary information. The embargo period may be extended by mutual agreement of the Sponsor and PI.
Publication restrictions are in place

Restriction type: OTHER

Measure	GRF6021 n=18 participants at risk Participants received 4 doses of GRF6021, 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 finally last dose was administered on the day after the surgery.	Placebo n=20 participants at risk 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.
Blood and lymphatic system disorders Haemorrhagic anaemia	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Cardiac disorders Tachycardia	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Eye disorders Eye irritation	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Gastrointestinal disorders Constipation	16.7% 3/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	10.0% 2/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Gastrointestinal disorders Dyspepsia	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Gastrointestinal disorders Vomiting	16.7% 3/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	15.0% 3/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Gastrointestinal disorders Nausea	38.9% 7/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	25.0% 5/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
General disorders Chest pain	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
General disorders Pyrexia	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Infections and infestations Pharyngitis	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Infections and infestations Stitch abscess	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Injury, poisoning and procedural complications Anaemia postoperative	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Injury, poisoning and procedural complications Incision site erythema	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Injury, poisoning and procedural complications Procedural haemorrhage	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Injury, poisoning and procedural complications Procedural vomiting	16.7% 3/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Investigations Blood pressure increased	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Investigations Gamma-glutamyl transferase increased	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Investigations Heart rate increased	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Nervous system disorders Headache	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Nervous system disorders Syncope	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Nervous system disorders Transient ischaemic attack	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Nervous system disorders Tremor	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Reproductive system and breast disorders Postmenopausal haemorrhage	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Skin and subcutaneous tissue disorders Swelling face	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Vascular disorders Hypotension	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	0.00% 0/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.
Vascular disorders Orthostatic hypotension	5.6% 1/18 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.	5.0% 1/20 • From Baseline (Day -7 to -3 prior to surgery) up to end of study (approximately Day 46) Safety population included all participants who received at least 1 dose of the study treatment.