A Two-part Phase I Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Target Engagement of Single Intravenous and Subcutaneous Doses of GSK3858279 in Healthy Participants and to Evaluate the Efficacy of Repeat Subcutaneous Doses in Participants With Osteoarthritis of the Knee
Overview
- Phase
- Phase 1
- Intervention
- GSK3858279 IV
- Conditions
- Pain, Inflammatory
- Sponsor
- GlaxoSmithKline
- Enrollment
- 97
- Locations
- 1
- Primary Endpoint
- Part A: Number of Participants With Clinically Significant Changes in Vital Signs
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This study is the first administration of GSK3858279 in humans and will be conducted in two parts: Part A will consist of a single ascending dose escalation design to evaluate safety, tolerability, PK, TE and immunogenicity of either a single intravenous (IV) or a single subcutaneous (SC) dose. Approximately 48 healthy participants will be enrolled in 6 cohorts and randomized to 3:1 ratio (GSK3858279 or placebo). Part B will evaluate safety, tolerability, efficacy (pain), PK, TE and immunogenicity after repeat SC dosing. Approximately 50 OA participants will be randomized in a parallel group design to receive either GSK3858279 or placebo in a 1:1 ratio.
Investigators
Eligibility Criteria
Inclusion Criteria
- •For Part A:
- •Participants between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- •Volunteers who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
- •Body weight within the range 50 to 100 kilogram (kg) and body mass index (BMI) within the range 18 to 32 kilogram per meter square (kg/m\^2) (inclusive).
- •Male participants are eligible to participate if they agree to the following for at least 28 weeks after the dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR must agree to use contraception/barrier as detailed below: agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
- •A female participant is eligible to participate if she is of non-reproductive potential.
- •Capable of giving signed informed consent.
- •For Part B:
- •Age between 40 and 75 years of age inclusive, at the time of signing the informed consent.
- •OA of the index knee as defined by symptomatic for \>=6 months with a clinical diagnosis of OA as per American College of Rheumatology (ACR) clinical diagnosis criteria.
Exclusion Criteria
- •For Part A:
- •History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
- •Personal or family history of cardiomyopathy.
- •Abnormal blood pressure at screening as determined by the investigator.
- •History of symptomatic herpes zoster.
- •Evidence of active or latent tuberculosis (TB) as documented by medical history, examination, and TB testing with a positive (not indeterminate) QuantiFERON test.
- •Significant allergies to humanized monoclonal antibodies as per principal investigator's and GlaxoSmithKline (GSK) medical monitor's judgments.
- •History or evidence of clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
- •Lymphoma, leukemia, or any malignancy except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
- •Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN).
Arms & Interventions
Part A: Cohort 1: GSK3858279
Eligible participants will receive GSK3858279 via IV route.
Intervention: GSK3858279 IV
Part A: Cohort 2: GSK3858279
Eligible participants will receive GSK3858279 via IV route.
Intervention: GSK3858279 IV
Part A: Cohort 3: GSK3858279
Eligible participants will receive GSK3858279 via IV route.
Intervention: GSK3858279 IV
Part A: Cohort 4: GSK3858279
Eligible participants will receive GSK3858279 via IV route.
Intervention: GSK3858279 IV
Part A: Cohort 5: GSK3858279
Eligible participants will receive GSK3858279 via IV route.
Intervention: GSK3858279 IV
Part A: Cohort 6: GSK3858279
Eligible participants will receive GSK3858279 via SC route.
Intervention: GSK3858279 SC
Part A: Placebo
Eligible participants will receive placebo matching to GSK3858279 via SC or IV route.
Intervention: Placebo matching to GSK3858279 (SC or IV)
Part B: GSK3858279
Eligible participants will receive GSK3858279 via SC route.
Intervention: GSK3858279 SC
Part B: Placebo
Eligible participants will receive placebo matching to GSK3858279 via SC route.
Intervention: Placebo matching to GSK3858279 (SC)
Outcomes
Primary Outcomes
Part A: Number of Participants With Clinically Significant Changes in Vital Signs
Time Frame: Up to 141 days
Vital signs included systolic and diastolic blood pressure, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring. Changes from baseline in vital signs were reviewed by the investigator, medical monitor and safety physician to determine clinical significance; the number of participants with clinically significant changes is reported.
Part B: Number of Participants With Clinically Significant Changes in Vital Signs
Time Frame: Up to 141 days
Vital signs included systolic and diastolic blood pressure, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring. Changes from baseline in vital signs were reviewed by the investigator, medical monitor and safety physician to determine clinical significance; the number of participants with clinically significant changes is reported.
Part B: Change From Baseline in Knee Pain as Assessed by Average of Daily Pain Numeric Rating Scale at Week 8
Time Frame: Baseline (Day 1) and Week 8
Change from Baseline in knee pain due to Osteoarthritis were reported by average of daily pain numeric rating scale (NRS) at Week 8. The pain NRS is an 11-point scale (ranging from 0-10) for self-reporting of average knee pain where 0 indicates no pain, and 10 indicates the worst possible pain. For each participant, the mean pain score prior to each visit was calculated as the average pain intensity in the 7 days prior to assessment visit. Participants were instructed to complete the pain NRS questionnaire at approximately the same time each day. A negative value change from baseline indicates an improvement. Baseline scores for each participant were assigned based on the first dosing visit.
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame: Up to 141 days
An Adverse Event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. TEAE is defined as an AE that occurred on or after the first dose date of study intervention. SAEs is defined as any serious adverse event that, at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, other situations as per investigator's medical or scientific judgment.
Part B: Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events
Time Frame: Up to 141 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. TEAE is defined as an AE that occurred on or after the first dose date of study intervention. SAEs is defined as any serious adverse event that, at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, other situations as per investigator's medical or scientific judgment.
Part A: Number of Participants With Clinically Significant Changes in Hematology, Clinical Chemistry Laboratory Parameters and Urinalysis
Time Frame: Up to 141 days
The parameters evaluated for Hematology were Basophils, Eosinophils, Hematocrit, Hemoglobin (Hg), Lymphocytes, mean corpuscular Hg, mean corpuscular volume, Monocytes, Platelet count, Red blood cells, Reticulocytes, Total Neutrophils, White blood cells count (WBC). For Clinical Chemistry- Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Bilirubin, Calcium, Creatinine, Direct bilirubin, Glucose, Potassium, Sodium, Total bilirubin, Total protein, TroponinT, N-terminal pro B-type natriuretic peptide (NT-ProBNP) and Urea. For Urinalysis-Urine bilirubin, Occult blood, Glucose, Ketones, Nitrates, pH, Protein, Specific gravity, Urobilinogen and Leukocyte Esterase for detecting WBC. Changes from baseline in hematology, clinical chemistry and urinalysis were reviewed by the investigator, medical monitor and safety physician to determine clinical significance; the number of participants with clinically significant changes is reported.
Part B: Number of Participants With Clinically Significant Changes in Hematology, Clinical Chemistry Laboratory Parameters and Urinalysis
Time Frame: Up to 141 days
The parameters evaluated for Hematology were Basophils, Eosinophils, Hematocrit, Hemoglobin (Hg), Lymphocytes, mean corpuscular Hg, mean corpuscular volume, Monocytes, Platelet count, Red blood cells, Reticulocytes, Total Neutrophils, White blood cells count (WBC). For Clinical Chemistry- Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Bilirubin, Calcium, Creatinine, Direct bilirubin, Glucose, Potassium, Sodium, Total bilirubin, Total protein, TroponinT, N-terminal pro B-type natriuretic peptide (NT-ProBNP) and Urea. For Urinalysis-Urine bilirubin, Occult blood, Glucose, Ketones, Nitrates, pH, Protein, Specific gravity, Urobilinogen and Leukocyte Esterase for detecting WBC. Changes from baseline in hematology, clinical chemistry and urinalysis were reviewed by the investigator, medical monitor and safety physician to determine clinical significance; the number of participants with clinically significant changes is reported.
Part A: Number of Participants With Clinically Significant Changes in Electrocardiogram Findings
Time Frame: Up to 141 days
Twelve-lead Electrocardiogram (ECG) were performed in a semi-supine position using an ECG machine that automatically calculates the heart rate and measures PR interval, QRS duration, Uncorrected QT and corrected QT intervals (QTc) intervals. Changes from baseline in ECG findings were reviewed by the investigator, medical monitor and safety physician to determine clinical significance; the number of participants with clinically significant changes is reported.
Part B: Number of Participants With Clinically Significant Changes in Electrocardiogram Findings
Time Frame: Up to 141 days
Twelve-lead Electrocardiogram (ECG) were performed in a semi-supine position using an ECG machine that automatically calculates the heart rate and measures PR interval, QRS duration, Uncorrected QT and corrected QT intervals (QTc) intervals. Changes from baseline in ECG findings were reviewed by the investigator, medical monitor and safety physician to determine clinical significance; the number of participants with clinically significant changes is reported.
Part B: Change From Baseline in Worst Knee Pain Intensity as Assessed by Numeric Rating Scale at Week 8
Time Frame: Baseline (Day 1) and Week 8
Change from Baseline in worst knee pain intensity were assessed using NRS at Week 8. The pain NRS is an 11-point scale (ranging from 0-10) for self-reporting of average knee pain where 0 indicated no pain, and 10 indicated worst possible pain. The mean pain score prior to each visit was calculated as the average pain intensity in the 7 days prior to assessment visit. Participants were instructed to complete the pain NRS questionnaire at approximately the same time each day. A negative value change from baseline indicates an improvement. Baseline scores for each participant were assigned based on the first dosing visit.
Secondary Outcomes
- Part A: Serum Concentrations of GSK3858279 Following a Single IV Dose(Up to 141 days)
- Part B: AUC(0-tau) Following a Repeat SC Dose of GSK3858279(Baseline and Week 8)
- Part B: Cmax After Repeat SC Dose of GSK3858279(Baseline and Week 8)
- Part A: Half-life (t1/2) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part A: Serum Concentrations of GSK3858279 Following a Single SC Dose(Up to 141 days)
- Part A: AUC From Zero to Time t (0-t) (AUC[0-t]) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part A: AUC From Zero to Time t (0-t) (AUC[0-t]) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part B: AUC(0-t) Following a Repeat SC Dose of GSK3858279(Up to 141 days)
- Part B: AUC(0-infinity) Following a Repeat SC Dose of GSK3858279(Up to 141 days)
- Part A: Volume of Distribution at Steady State (Vss) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part B: Vss Following a Repeat SC Dose of GSK3858279(Up to 141 days)
- Part A: Volume of Distribution (V) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part A: Volume of Distribution (V) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part A: Free Chemokine Ligand 17 (CCL17) Levels in Serum Following Single IV Dose of GSK3858279(Up to 141 days)
- Part A: Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-tau) (AUC[0-tau]) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part B: Volume of Distribution (V) Following a Repeat SC Dose of GSK3858279(Up to 141 days)
- Part B: Serum Concentration of GSK3858279 Following Repeat SC Dose(Up to 141 days)
- Part A: AUC From Zero to Infinity (0-infinity) (AUC[0-infinity]) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part A: AUC(0-tau) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part A: Maximum Concentration (Cmax) After a Single IV Dose of GSK3858279(Up to 141 days)
- Part B: CL Following a Repeat SC Dose of GSK3858279(Up to 141 days)
- Part A: Volume of Distribution at Steady State (Vss) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part A: AUC From Zero to Infinity (0-infinity) (AUC[0-infinity]) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part A: Maximum Concentration (Cmax) After a Single SC Dose of GSK3858279(Up to 141 days)
- Part A: Half-life (t1/2) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part B: t1/2 Following a Repeat SC Dose of GSK3858279(Up to 141 days)
- Part A: Clearance (CL) Following a Single IV Dose of GSK3858279(Up to 141 days)
- Part A: Clearance (CL) Following a Single SC Dose of GSK3858279(Up to 141 days)
- Part A: CCL17 Levels in Serum Following Single SC Dose of GSK3858279(Up to 141 days)
- Part B: Free CCL17 Levels in Serum Following Repeat SC Dose of GSK3858279(Up to 141 days)
- Part A: Total CCL17 Levels in Serum Following Single IV Dose of GSK3858279(Up to 141 days)
- Part B: Total CCL17 Levels in Serum Following Repeat SC Dose of GSK3858279(Up to 141 days)
- Part A: Total CCL17 Levels in Serum Following Single SC Dose of GSK3858279(Up to 141 days)