A Safety, Tolerability, Pharmacokinetics (PK) and Target Engagement (TE) Study of GSK3858279 in Healthy Participants and Evaluation of the Efficacy of Repeat Doses in Participants With Osteoarthritis (OA)

NCT03485365 | Completed Phase 1 Results

• 2 other identifiers: 2078042017-004809-41
• Study Type: interventional
• Target: 97
• Locations: 3 countries
• Sites: 5

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.

Conditions

Pain, Inflammatory

Keywords

Pain; Osteoarthritis of the knee; Target engagement; GSK3858279; Pharmacokinetics; Sequential

Outcome Measures

Primary Outcomes (10)

• Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

  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.

  Up to 141 days

• Part B: Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

  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.

  Up to 141 days

• Part A: Number of Participants With Clinically Significant Changes in Hematology, Clinical Chemistry Laboratory Parameters and Urinalysis

  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.

  Up to 141 days

• Part B: Number of Participants With Clinically Significant Changes in Hematology, Clinical Chemistry Laboratory Parameters and Urinalysis

  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.

  Up to 141 days

• Part A: Number of Participants With Clinically Significant Changes in Electrocardiogram Findings

  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.

  Up to 141 days

• Part B: Number of Participants With Clinically Significant Changes in Electrocardiogram Findings

  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.

  Up to 141 days

• Part A: Number of Participants With Clinically Significant Changes in Vital Signs

  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.

  Up to 141 days

• Part B: Number of Participants With Clinically Significant Changes in Vital Signs

  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.

  Up to 141 days

• Part B: Change From Baseline in Knee Pain as Assessed by Average of Daily Pain Numeric Rating Scale at 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.

  Baseline (Day 1) and Week 8

• Part B: Change From Baseline in Worst Knee Pain Intensity as Assessed by Numeric Rating Scale at 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.

  Baseline (Day 1) and Week 8

Secondary Outcomes (33)

• Part A: Serum Concentrations of GSK3858279 Following a Single IV Dose

  Up to 141 days

• Part A: Serum Concentrations of GSK3858279 Following a Single SC Dose

  Up to 141 days

• Part B: Serum Concentration of GSK3858279 Following Repeat SC Dose

  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 A: AUC From Zero to Time t (0-t) (AUC[0-t]) Following a Single IV Dose of GSK3858279

  Up to 141 days

Study Arms (9)

Part A: Cohort 1: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via IV route.

Drug: GSK3858279 IV

Part A: Cohort 2: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via IV route.

Drug: GSK3858279 IV

Part A: Cohort 3: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via IV route.

Drug: GSK3858279 IV

Part A: Cohort 4: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via IV route.

Drug: GSK3858279 IV

Part A: Cohort 5: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via IV route.

Drug: GSK3858279 IV

Part A: Cohort 6: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via SC route.

Drug: GSK3858279 SC

Part A: Placebo

PLACEBO COMPARATOR

Eligible participants will receive placebo matching to GSK3858279 via SC or IV route.

Drug: Placebo matching to GSK3858279 (SC or IV)

Part B: GSK3858279

EXPERIMENTAL

Eligible participants will receive GSK3858279 via SC route.

Drug: GSK3858279 SC

Part B: Placebo

PLACEBO COMPARATOR

Eligible participants will receive placebo matching to GSK3858279 via SC route.

Drug: Placebo matching to GSK3858279 (SC)

Interventions

GSK3858279 IV DRUG

GSK3858279 will be available as solution for injection to be administered via IV route.

Part A: Cohort 1: GSK3858279; Part A: Cohort 2: GSK3858279; Part A: Cohort 3: GSK3858279; Part A: Cohort 4: GSK3858279; Part A: Cohort 5: GSK3858279

GSK3858279 SC DRUG

GSK3858279 will be available as solution for injection to be administered via SC route.

Part A: Cohort 6: GSK3858279; Part B: GSK3858279

Placebo matching to GSK3858279 (SC or IV) DRUG

Placebo will be available as sodium chloride solution to be administered via SC or IV route.

Part A: Placebo

Placebo matching to GSK3858279 (SC) DRUG

Placebo will be available as sodium chloride solution to be administered via SC route.

Part B: Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Average of daily pain score \>=4 and \<=9 by 11 point NRS (0 to 10) in index knee over 7 days prior to dosing (Day-7 to Day-1). Data should be recorded on at least 5 of 7 occasions by the participant to obtain a valid Baseline value.
• Kellgren and Lawrence (KL) score \>=2 on X-ray obtained during screening. In addition, for participants with bilateral Knee OA, the index knee is determined at Baseline as the participant reported most painful knee over the 4 weeks prior to Baseline.
• A history of insufficient pain relief from, or inability to tolerate, or contraindication to, oral Non-steroidal anti-inflammatory drugs (NSAIDs).
• A participant must be willing and able to understand and participate in all scheduled evaluations and to complete all required tests and procedures including the use of patient diaries. This will be judged by the Investigator during the screening period.
• BMI within the range 19-34.9 kg/m\^2 (inclusive)

You may not qualify if:

• 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).
• Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Corrected QT (QTc) \>450 milliseconds (msec).
• History of Stevens Johnson Syndrome.
• Known immunodeficiency.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (5)

GSK Investigational Site

Berlin, 10117, Germany

Location

GSK Investigational Site

Warsaw, 02-106, Poland

Location

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

GSK Investigational Site

Manchester, M13 9NQ, United Kingdom

Location

MeSH Terms

Conditions

Pain; Osteoarthritis, Knee

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Limitations and Caveats

Data has not been disclosed for pharmacokinetic parameters for this study as the development of the compound (GSK3858279) is still ongoing in another phase II study (NCT05838742) to fully understand the PK trends/parameters. We will disclose data for all pre-specified secondary PK parameters by 15-DEC-2027.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This will be a double blind study. Participant and investigator will be masked.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants will be randomized in 3:1 ratio to receive GSK3858279 and placebo in sequential manner in Part A. In Part B, participants will be randomized in parallel groups to receive either GSK3858279 or placebo.

Study Record Dates

• First Submitted: March 27, 2018
• First Posted: April 2, 2018
• Study Start: May 17, 2018
• Primary Completion: September 12, 2022
• Study Completion: September 12, 2022
• Last Updated: March 22, 2024
• Results First Posted: March 22, 2024

Record last verified: 2023-09

Locations

DE (1); PL (1); GB (3)