Postoperative Recovery
Conditions
Keywords
Total hip replacement, Total knee replacement
Brief summary
This study will evaluate the safety, tolerability and effect of GRF6021 on clinical recovery parameters in participants undergoing primary hip or knee arthroplasty.
Detailed description
This is a randomized, placebo-controlled, double-blind pilot study to investigate the effects of GRF6021, a 5% human plasma protein fraction administered by intravenous (IV) infusion, on intracellular signaling cascades in blood leukocytes in participants undergoing primary hip or knee arthroplasty.
Interventions
BIOLOGICALGRF6021
for IV infusion
OTHERPlacebo
for IV infusion
Sponsors
Alkahest, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Men and women 50-85 years of age scheduled to undergo primary total hip or knee replacement surgery. * Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 .
Exclusion criteria
* Blood coagulation disorders. * Participants who started chronic anticoagulant therapy (warfarin, heparin, low-molecular weight heparin, or Factor Xa inhibitors) in the last 6 months * Hypercoagulable state. * Prior hypersensitivity to any human blood product including plasma. * Treatment with any human blood product, including transfusions and IV immunoglobulin, during the 6 months prior to screening. * History of immunoglobulin A or haptoglobin deficiency. * Major surgery, trauma or injury in the last 3 months or minor surgery in the last 1 month. * Heart disease or congestive heart failure in the 6 months prior to dosing. * Poorly controlled hypertension. * Severe anemia. * Functional impairment of major joint or lower extremity other than joint undergoing surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 2 | Day 2 (before start of surgery and post surgery) | 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. |
| Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 3 | Day 3 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 (Day 1 pre-infusion); Days 2 (post-infusion), and 3 (pre-infusion) | 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. |
| Time to 50% Recovery of Baseline Value on the Surgery Recovery Scale (SRS) | Baseline; Days 1 and 3 (pre-infusion) and thereafter up to the end of the study (approximately Day 46) | 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. |
| End of Study (EOS) Treatment Comparison of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) | At end of study (approximately Day 46) | 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. |
| Time to a Score of < 12/40 on a Subset of Questions From the WOMAC, Pain Subscale | Days 1 and 3 (pre-infusion) and thereafter up to Day 39 | 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. |
| Time to a Score of < 18/60 on a Subset of Questions From the WOMAC, Physical Function Subscale | Days 1 and 3 (pre-infusion) and thereafter up to Day 39 | 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. |
| Change From Baseline in Mental Health Score in the Short Form-36 (SF-36) | At Baseline and end of study (approximately Day 46) | 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. |
| Number of Participants With Abnormal Laboratory Blood Chemistry Values | At Screening and Day 3 | 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. |
| Change From Baseline in Physical Health Score in the SF-36 | At Baseline and end of study (approximately Day 46) | 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. |
| Change From Baseline in the Beck Depression Inventory-II (BDI-II) | At Baseline and end of study (approximately Day 46) | 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. |
| Number of Participants With Opioid Analgesic Consumption During Hospital Stay and After Discharge to End of Study | From Day 2 (post-surgery) up to end of study (approximately Day 46) | — |
| Time to Discharge | Day 1 up to end of study (approximately Day 46) | 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). |
| Perioperative Outcome: Surgery Duration | Day 2 | The duration (in hours) for which a participant underwent surgery i.e., primary hip or knee arthroplasty is reported here. |
| Perioperative Outcome: Duration for Which Participants Were Under Anesthesia | Day 2 | The duration (in hours) for which a participant was under anesthesia is reported here. |
| Change in Functional Status Using the ActiGraph Wearable Device Providing Measurements for Physical Activity/Function and Sleep | Baseline; Day 1, Day 3 up to approximately Day 46 | 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. |
| Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | Day 2 | 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. |
| Perioperative Outcome: Estimated Blood Loss | Day 2 | — |
| Number of Participants in Whom Intraoperative Fluids Were Administered | Day 2 | Intraoperative fluids administered were summarized by WHO Drug Dictionary (WHO-DD) Version 2018 Anatomical Therapeutic Chemical (ATC) level 3 terms and standardized medication names. |
| Number of Participants in Whom Intraoperative Blood Products Were Administered | Day 2 | Intraoperative blood products administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names. |
| Number of Participants Who Received Intraoperative Anesthesia | Day 2 | Intraoperative anesthesia administered were summarized using WHO-DD Version 2018 ATC level 3 terms and standardized medication names. |
| Number of Participants Who Received Intraoperative Opioids | Day 2 | The number of participants with intraoperative opioids administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names. |
| Number of Participants With Abnormal Laboratory Hematology Values | Day 3 | 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%. |
| Number of Participants With Abnormal Laboratory Coagulation Values | At Screening and Day 3 | 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. |
| Number of Participants With Abnormal Laboratory Urinalysis Values | At Screening and Day 3 | 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. |
| Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | 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 | 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. |
| Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate | Baseline (Day 1 pre-infusion); Day 3 pre and post-infusion | A 12-lead ECG was to be performed to obtain heart rate. The baseline was defined as Day 1 pre-infusion measurement. |
| Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) | Baseline (Day 1 pre-infusion); Day 3 pre and post-infusion | 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. |
| Perioperative Outcome: Duration of Stay in the Post-Anesthesia Care Unit (PACU) | Day 2 | The duration (in hours) for which the participants stayed at the PACU is reported here. |
| Effects of GRF6021 on Plasma Proteomics | Pre-infusion on Day 1 (baseline), 2 (before start of surgery and post surgery), and Day 3 | 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in this study at one investigative site in the United States from 12 July 2019 to 04 March 2021.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| GRF6021 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. | 18 |
| 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. | 20 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Due to Coronavirus Disease-2019 (COVID-19) | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | GRF6021 |
|---|---|---|---|
| Age, Continuous | 65.40 years STANDARD_DEVIATION 8.39 | 67.89 years STANDARD_DEVIATION 7.7 | 70.70 years STANDARD_DEVIATION 5.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 37 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 24 Participants | 8 Participants |
| Sex: Female, Male Female | 10 Participants | 19 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 20 |
| other Total, other adverse events | 14 / 18 | 14 / 20 |
| serious Total, serious adverse events | 0 / 18 | 0 / 20 |
Outcome results
Primary
Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 2
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GRF6021 | 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 |
| GRF6021 | 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 |
| Placebo | 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) | 0.4521 predicted value |
| Placebo | Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 2 | Day 2 (Post Surgery) | 0.4471 predicted value |
Primary
Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 3
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 3 | 0.7829 predicted value |
| Placebo | Effect of GRF6021 on Immune Responses to Surgery as Determined by Cytometry by Time of Flight (CyTOF) on Day 3 | 0.2871 predicted value |
Secondary
Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| Placebo | 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) | -1.3 msec | Standard Deviation 23.71 |
| Placebo | Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) | QT Interval: At Baseline | 408.9 msec | Standard Deviation 26.02 |
| Placebo | Change From Baseline in ECG Parameters: QT Interval and QT Interval Corrected by the Fridericia Formula (QTcF) | QTcF: At Baseline | 416.4 msec | Standard Deviation 16.68 |
| Placebo | 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) | -9.3 msec | Standard Deviation 37.04 |
| Placebo | 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) | -4.1 msec | Standard Deviation 14.91 |
| Placebo | 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) | -15.6 msec | Standard Deviation 31.01 |
Secondary
Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate
A 12-lead ECG was to be performed to obtain heart rate. The baseline was defined as Day 1 pre-infusion measurement.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GRF6021 | Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate | At Baseline | 63.7 beats/minute | Standard Deviation 7.05 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate | At Baseline | 64.5 beats/minute | Standard Deviation 11.24 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate | Change From Baseline on Day 3 (Prior to Infusion) | 5.1 beats/minute | Standard Deviation 11.08 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate | Change From Baseline on Day 3 (Post Infusion) | 5.7 beats/minute | Standard Deviation 11.96 |
Secondary
Change From Baseline in Mental Health Score in the Short Form-36 (SF-36)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GRF6021 | 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 |
| GRF6021 | 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 |
| Placebo | Change From Baseline in Mental Health Score in the Short Form-36 (SF-36) | Baseline | 57.6 score on a scale | Standard Deviation 8.5 |
| Placebo | Change From Baseline in Mental Health Score in the Short Form-36 (SF-36) | Change From Baseline at End of Study | 0.8 score on a scale | Standard Deviation 8.62 |
Secondary
Change From Baseline in Physical Health Score in the SF-36
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GRF6021 | Change From Baseline in Physical Health Score in the SF-36 | Baseline | 32.7 score on a scale | Standard Deviation 6.87 |
| GRF6021 | 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 |
| Placebo | Change From Baseline in Physical Health Score in the SF-36 | Baseline | 34.9 score on a scale | Standard Deviation 9.68 |
| Placebo | Change From Baseline in Physical Health Score in the SF-36 | Change From Baseline at End of Study | 3.3 score on a scale | Standard Deviation 9.9 |
Secondary
Change From Baseline in the Beck Depression Inventory-II (BDI-II)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GRF6021 | Change From Baseline in the Beck Depression Inventory-II (BDI-II) | Baseline | 7.3 score on a scale | Standard Deviation 9.47 |
| GRF6021 | 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 |
| Placebo | Change From Baseline in the Beck Depression Inventory-II (BDI-II) | Baseline | 5.1 score on a scale | Standard Deviation 5.47 |
| Placebo | Change From Baseline in the Beck Depression Inventory-II (BDI-II) | Change From Baseline at End of Study | -2.7 score on a scale | Standard Deviation 5.65 |
Secondary
Change in Functional Status Using the ActiGraph Wearable Device Providing Measurements for Physical Activity/Function and Sleep
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Change in Functional Status Using the ActiGraph Wearable Device Providing Measurements for Physical Activity/Function and Sleep | 1.7007 predicted value |
| Placebo | Change in Functional Status Using the ActiGraph Wearable Device Providing Measurements for Physical Activity/Function and Sleep | 1.3861 predicted value |
Secondary
Effects of GRF6021 on Plasma Proteomics
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| GRF6021 | Effects of GRF6021 on Plasma Proteomics | Day 1 (Baseline) | 1.4320 predicted value |
| GRF6021 | Effects of GRF6021 on Plasma Proteomics | Day 2 (Before Surgery Start) | 1.4189 predicted value |
| GRF6021 | Effects of GRF6021 on Plasma Proteomics | Day 2 (Post Surgery) | 1.1563 predicted value |
| GRF6021 | Effects of GRF6021 on Plasma Proteomics | Day 3 | 1.3971 predicted value |
| Placebo | Effects of GRF6021 on Plasma Proteomics | Day 3 | 1.6284 predicted value |
| Placebo | Effects of GRF6021 on Plasma Proteomics | Day 1 (Baseline) | 1.3716 predicted value |
| Placebo | Effects of GRF6021 on Plasma Proteomics | Day 2 (Post Surgery) | 1.7264 predicted value |
| Placebo | Effects of GRF6021 on Plasma Proteomics | Day 2 (Before Surgery Start) | 1.5245 predicted value |
Secondary
End of Study (EOS) Treatment Comparison of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GRF6021 | 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 |
| Placebo | End of Study (EOS) Treatment Comparison of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) | 37.30 score on a scale | Standard Deviation 38.8 |
Secondary
Number of Participants in Whom Intraoperative Blood Products Were Administered
Intraoperative blood products administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRF6021 | Number of Participants in Whom Intraoperative Blood Products Were Administered | 0 Participants |
| Placebo | Number of Participants in Whom Intraoperative Blood Products Were Administered | 0 Participants |
Secondary
Number of Participants in Whom Intraoperative Fluids Were Administered
Intraoperative fluids administered were summarized by WHO Drug Dictionary (WHO-DD) Version 2018 Anatomical Therapeutic Chemical (ATC) level 3 terms and standardized medication names.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRF6021 | Number of Participants in Whom Intraoperative Fluids Were Administered | 0 Participants |
| Placebo | Number of Participants in Whom Intraoperative Fluids Were Administered | 0 Participants |
Secondary
Number of Participants Who Received Intraoperative Anesthesia
Intraoperative anesthesia administered were summarized using WHO-DD Version 2018 ATC level 3 terms and standardized medication names.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Number of Participants Who Received Intraoperative Anesthesia | General Anesthesia | 18 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Anesthesia | Local Anesthesia | 15 Participants |
| Placebo | Number of Participants Who Received Intraoperative Anesthesia | Local Anesthesia | 19 Participants |
| Placebo | Number of Participants Who Received Intraoperative Anesthesia | General Anesthesia | 19 Participants |
Secondary
Number of Participants Who Received Intraoperative Opioids
The number of participants with intraoperative opioids administered were summarized by WHO-DD Version 2018 ATC level 3 terms and standardized medication names.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Oxycodone hydrochloride | 1 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Hydrocodone | 2 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Codeine | 1 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Oxycodone | 17 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Hydromorphone hydrochloride | 0 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Tramadol | 2 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Tramadol hydrochloride | 0 Participants |
| GRF6021 | Number of Participants Who Received Intraoperative Opioids | Hydromorphone | 9 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Tramadol hydrochloride | 1 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Oxycodone | 19 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Hydrocodone | 3 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Tramadol | 3 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Oxycodone hydrochloride | 2 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Codeine | 0 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Hydromorphone hydrochloride | 1 Participants |
| Placebo | Number of Participants Who Received Intraoperative Opioids | Hydromorphone | 6 Participants |
Secondary
Number of Participants With Abnormal Laboratory Blood Chemistry Values
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.
Time frame: At Screening and Day 3
Population: Safety population consisted of all participants who received at least 1 dose of the study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Number of Participants With Abnormal Laboratory Blood Chemistry Values | Screening: Calcium, Ionized (mmol/L): High > 1.47 | 1 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Blood Chemistry Values | Day 3: Calcium, Ionized (mmol/L): Low < 1.12 | 0 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Blood Chemistry Values | Day 3: Sodium (mmol/L): Low < 130 | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Blood Chemistry Values | Screening: Calcium, Ionized (mmol/L): High > 1.47 | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Blood Chemistry Values | Day 3: Calcium, Ionized (mmol/L): Low < 1.12 | 1 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Blood Chemistry Values | Day 3: Sodium (mmol/L): Low < 130 | 1 Participants |
Secondary
Number of Participants With Abnormal Laboratory Coagulation Values
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.
Time frame: At Screening and Day 3
Population: Safety population consisted of all participants who received at least 1 dose of the study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Number of Participants With Abnormal Laboratory Coagulation Values | At Screening: Prothrombin Time (seconds): High > 20 | 1 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Coagulation Values | Day 3: Prothrombin International Normalized Ratio: High > 1.3 | 4 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Coagulation Values | Day 3: Activated Partial Thromboplastin Time (seconds): High > 45 | 0 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Coagulation Values | Day 3: Prothrombin Time (seconds): High > 20 | 2 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Coagulation Values | At Screening: Prothrombin International Normalized Ratio: High > 1.3 | 1 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Coagulation Values | Day 3: Prothrombin Time (seconds): High > 20 | 3 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Coagulation Values | At Screening: Prothrombin International Normalized Ratio: High > 1.3 | 1 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Coagulation Values | At Screening: Prothrombin Time (seconds): High > 20 | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Coagulation Values | Day 3: Activated Partial Thromboplastin Time (seconds): High > 45 | 2 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Coagulation Values | Day 3: Prothrombin International Normalized Ratio: High > 1.3 | 3 Participants |
Secondary
Number of Participants With Abnormal Laboratory Hematology Values
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%.
Time frame: Day 3
Population: Safety population consisted of all participants who received at least 1 dose of the study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Number of Participants With Abnormal Laboratory Hematology Values | Day 3: Hematocrit (%): Low < 30 | 6 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Hematology Values | Day 3: Hemoglobin (g/dL): Low < 10 | 8 Participants |
| GRF6021 | Number of Participants With Abnormal Laboratory Hematology Values | Day 3: Lymphocytes/Leukocytes (%): Low < 10 | 3 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Hematology Values | Day 3: Hematocrit (%): Low < 30 | 1 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Hematology Values | Day 3: Hemoglobin (g/dL): Low < 10 | 4 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Hematology Values | Day 3: Lymphocytes/Leukocytes (%): Low < 10 | 3 Participants |
Secondary
Number of Participants With Abnormal Laboratory Urinalysis Values
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.
Time frame: At Screening and Day 3
Population: Safety population consisted of all participants who received at least 1 dose of the study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRF6021 | Number of Participants With Abnormal Laboratory Urinalysis Values | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Urinalysis Values | 0 Participants |
Secondary
Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 1 (Prior to Infusion) | 1 Participants |
| GRF6021 | 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 |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (Prior to Infusion) | 1 Participants |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 2 Postoperative (Prior to Infusion) | 1 Participants |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (Prior to Infusion) | 0 Participants |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (15 Minutes Post Infusion) | 0 Participants |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (30 Minutes Post Infusion) | 0 Participants |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (45 Minutes Post Infusion) | 1 Participants |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (60 Minutes Post Infusion) | 1 Participants |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (Prior to Infusion) | 1 Participants |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (15 Minutes Post Infusion) | 0 Participants |
| GRF6021 | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (30 Minutes Post Infusion) | 1 Participants |
| GRF6021 | 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 |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (15 Minutes Post Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 1 (Prior to Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (15 Minutes Post Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 1 (30 Minutes After End of Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (30 Minutes Post Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (Prior to Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 2 Postoperative (30 Minutes Post Infusion) | 1 Participants |
| Placebo | 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 |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (45 Minutes Post Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (30 Minutes Post Infusion) | 2 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (30 Minutes After End of Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 2 Preoperative (45 Minutes Post Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (60 Minutes Post Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 180 mmHg: On Day 2 Postoperative (Prior to Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (Prior to Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 200 mmHg: On Day 2 Preoperative (15 Minutes Post Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (30 Minutes After End of Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Systolic Blood Pressure > 200 mmHg: On Day 2 Preoperative (30 Minutes Post Infusion) | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 3 (30 Minutes Post Infusion) | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs: Blood Pressure Measurements | Diastolic Blood Pressure < 50 mmHg: On Day 1 (Prior to Infusion) | 1 Participants |
| Placebo | 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) | 2 Participants |
Secondary
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])
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| GRF6021 | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 | 19 Participants |
| Placebo | 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 | 19 Participants |
| Placebo | 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 | 19 Participants |
| Placebo | 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 | 0 Participants |
Secondary
Number of Participants With Opioid Analgesic Consumption During Hospital Stay and After Discharge to End of Study
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRF6021 | Number of Participants With Opioid Analgesic Consumption During Hospital Stay and After Discharge to End of Study | 18 Participants |
| Placebo | Number of Participants With Opioid Analgesic Consumption During Hospital Stay and After Discharge to End of Study | 19 Participants |
Secondary
Perioperative Outcome: Duration for Which Participants Were Under Anesthesia
The duration (in hours) for which a participant was under anesthesia is reported here.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Perioperative Outcome: Duration for Which Participants Were Under Anesthesia | 3.0 hours |
| Placebo | Perioperative Outcome: Duration for Which Participants Were Under Anesthesia | 2.7 hours |
Secondary
Perioperative Outcome: Duration of Stay in the Post-Anesthesia Care Unit (PACU)
The duration (in hours) for which the participants stayed at the PACU is reported here.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Perioperative Outcome: Duration of Stay in the Post-Anesthesia Care Unit (PACU) | 2.6 hours |
| Placebo | Perioperative Outcome: Duration of Stay in the Post-Anesthesia Care Unit (PACU) | 2.9 hours |
Secondary
Perioperative Outcome: Estimated Blood Loss
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GRF6021 | Perioperative Outcome: Estimated Blood Loss | 113.6 mL | Standard Deviation 60 |
| Placebo | Perioperative Outcome: Estimated Blood Loss | 135.8 mL | Standard Deviation 96.63 |
Secondary
Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class
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.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GRF6021 | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA Il | 8 Participants |
| GRF6021 | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA IV | 0 Participants |
| GRF6021 | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA III | 10 Participants |
| GRF6021 | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA V | 0 Participants |
| GRF6021 | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA I | 0 Participants |
| Placebo | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA V | 0 Participants |
| Placebo | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA I | 0 Participants |
| Placebo | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA Il | 12 Participants |
| Placebo | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA III | 7 Participants |
| Placebo | Perioperative Outcome: Number of Participants in Each 5 American Society of Anesthesiologists (ASA) Class | ASA IV | 0 Participants |
Secondary
Perioperative Outcome: Surgery Duration
The duration (in hours) for which a participant underwent surgery i.e., primary hip or knee arthroplasty is reported here.
Time frame: Day 2
Population: Evaluable population included all participants who received all 4 doses of study treatment and in whom all blood samples were collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Perioperative Outcome: Surgery Duration | 1.8 hours |
| Placebo | Perioperative Outcome: Surgery Duration | 1.6 hours |
Secondary
Time to 50% Recovery of Baseline Value on the Surgery Recovery Scale (SRS)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Time to 50% Recovery of Baseline Value on the Surgery Recovery Scale (SRS) | 11.5 days |
| Placebo | Time to 50% Recovery of Baseline Value on the Surgery Recovery Scale (SRS) | 15.0 days |
Secondary
Time to a Score of < 12/40 on a Subset of Questions From the WOMAC, Pain Subscale
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Time to a Score of < 12/40 on a Subset of Questions From the WOMAC, Pain Subscale | 13.5 days |
| Placebo | Time to a Score of < 12/40 on a Subset of Questions From the WOMAC, Pain Subscale | 16.0 days |
Secondary
Time to a Score of < 18/60 on a Subset of Questions From the WOMAC, Physical Function Subscale
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Time to a Score of < 18/60 on a Subset of Questions From the WOMAC, Physical Function Subscale | 18.0 days |
| Placebo | Time to a Score of < 18/60 on a Subset of Questions From the WOMAC, Physical Function Subscale | 18.0 days |
Secondary
Time to Discharge
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GRF6021 | Time to Discharge | 2.0 days |
| Placebo | Time to Discharge | 2.0 days |