A Study of the Efficacy and Safety of MEDI7352 in Participants With Painful Osteoarthritis of the Knee

Phase 2

Completed

Conditions: Painful Osteoarthritis of the Knee

Interventions: Drug: MEDI7352
Other: Placebo

Registration Number: NCT04675034

Lead Sponsor: AstraZeneca

Brief Summary: This is a Phase IIb randomised, double-blind, placebo-controlled, dose-response study in participants with painful osteoarthritis (OA) of the knee. The study will assess the safety and efficacy of multiple doses of MEDI7352 compared to placebo, as well as the pharmacokinetics, pharmacodynamics and immunogenicity of MEDI7352 in participants with moderate to severe chronic pain persistent for 3 months or more not adequately controlled by standard of care treatments.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 345

Inclusion Criteria

Participants must understand the nature of the study and must give signed and dated written informed consent prior to the initiation of any study procedures, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
For participants participating in the optional genetic research, a separate signed and dated optional genetic research ICF must be provided prior to collection of samples for optional genetic research that supports the Genomics Initiative. If a participant declines to participate in the genetic research, this will have no influence on the ability of a participant to participate in the study.
The participant should be willing and able to understand and comply with all protocol-specified restrictions and procedures and be able to use an electronic patient-reported outcome (ePRO) device as judged by the investigator.
The participant must be considered likely to comply with the study protocol and to have a high probability of completing the study, as judged by the investigator.
The participant must be willing and able to discontinue all analgesic therapy with nonsteroidal anti-inflammatory drugs (NSAID) or cyclooxygenase-2 (COX-2) inhibitors from the start of the washout period until the end of the FU period. This includes over-the-counter (OTC) pain medications and topical analgesics that contain an NSAID or COX-2 inhibitor.

Exclusion Criteria

Requires current treatment with another biologic therapeutic agent, disease-modifying antirheumatic drug (DMARD), or other immunosuppressants.
Previously received any form of anti-nerve growth factor (NGF); received anti-tumour necrosis factors (TNFs) including but not limited to golimumab, certolizumab, infliximab, adalimumab, etanercept, or rituximab within 12 months prior to screening, or other biological DMARDs (including but not limited to abatacept, tocilizumab, and tofacitinib), or other immunosuppressants within 6 months prior to screening (with the exception of inhaled or topical corticosteroids).
Currently receiving strong opioids for any indication.
Participation in another clinical study with an IP or device within 60 days or 5 half-lives, whichever is longer, prior to screening.
Plasma donation within 28 days of screening or any blood donation or blood loss > 500 mL within 2 months of screening.
Previous allogeneic bone marrow or stem cell transplant.
Received nonleukocyte-depleted whole blood transfusion within 120 days of the genetic research sample collection, if participating in the optional genetic research.
Involvement in the planning and/or conduct of the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MEDl7352 Dose 1	MEDI7352	Participants received 6 doses of subcutaneous (SC) MEDl7352 Dose 1 injection once every 2 weeks (Q2W) during a 12-week parallel-group treatment period.
Placebo	Placebo	Participants received 6 doses of SC placebo injection matched to MEDl7352 Q2W during a 12-week parallel-group treatment period.
MEDl7352 Dose 3	MEDI7352	Participants received 6 doses of SC MEDl7352 Dose 3 injection Q2W during a 12-week parallel-group treatment period.
Cohort 1	MEDI7352	Dose A: MEDI7352 Q2W
Cohort 3	MEDI7352	Dose C: MEDI7352 Q2W
Cohort 2	MEDI7352	Dose B: MEDI7352 Q2W
Cohort 4	MEDI7352	Dose D: MEDI7352 Q2W
Cohort 5:	Placebo	Placebo to match MEDI7352 Q2W
MEDl7352 Dose 2	MEDI7352	Participants received 6 doses of SC MEDl7352 Dose 2 injection Q2W during a 12-week parallel-group treatment period.
MEDl7352 Dose 4	MEDI7352	Participants received 6 doses of SC MEDl7352 Dose 4 injection Q2W during a 12-week parallel-group treatment period.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Weekly Average of Daily Numerical Rating Scale (NRS) Pain Score to Week 12	Baseline (Day -7 to Day -1, inclusive) through Week 12	Change from baseline in weekly average of daily NRS pain score to Week 12 is reported. The NRS is an 11-point Likert scale used to assess pain, where participants were asked to describe their average pain in the target knee by identifying a number from 0 = "no pain" to 10 = "most severe pain imaginable over the previous 24 hours". This was recorded on a daily basis at approximately the same time every morning via electronic patient recorded outcome (ePRO) diary. A two-step multiple imputation procedure was used to address missing post-baseline scores.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale to Week 12	Week 0 (Day 1; baseline) through Week 12	The WOMAC multiscale index is used to assess pain, stiffness, and joint functionality in the past 48 hours in participants with OA of the knee or hip. The WOMAC pain subscale consists of 5 questions assessing the participant's pain due to osteoarthritis (OA) in the target knee. Each question was scored on a NRS scale from 0 to 10, and the WOMAC pain subscale score is calculated as the mean score from all 5 questions, where higher scores represent higher pain. Change from baseline in WOMAC pain subscale to Week 12 is reported. A two-step multiple imputation procedure was used to address missing post-baseline scores.
Change From Baseline in WOMAC Physical Function Subscale to Week 12	Week 0 (Day 1; baseline) through Week 12	The WOMAC multiscale index is used to assess pain, stiffness, and joint functionality in the past 48 hours in participants with OA of the knee or hip. The WOMAC physical function (PF) subscale consists of 17 questions assessing the participant's difficulty in performing activities of daily living due to OA in the target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC PF subscale score is calculated as the mean score from all 17 questions, where higher scores represent worse function. Change from baseline in WOMAC physical function to Week 12 is reported. A two-step multiple imputation procedure was used to address missing post-baseline scores.
Change From Baseline in Patient's Global Assessment (PGA) of OA to Week 12	Week 0 (Day 1; baseline) through Week 12	The PGA of OA was a 5-point Likert scale used to assess symptoms and activity impairment due to OA of the knee. Participants were asked to identify a number from 1 = "very good (asymptomatic and no limitation to normal activities)" to 5 = "very poor (very severe symptoms which are intolerable and inability to carry out all normal activities)" based on the question "Considering all the ways that OA of the knee affects you, how are you feeling today?". Change from baseline in PGA of OA to Week 12 is reported. A two-step multiple imputation procedure was used to address missing post-baseline scores.
Change From Baseline in WOMAC Pain Subscale Over Time	Baseline (Week 0; Day 1), Weeks 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), and 18 (Day 126)	The WOMAC multiscale index is used to assess pain, stiffness, and joint functionality in the past 48 hours in participants with OA of the knee or hip. The WOMAC pain subscale consists of 5 questions assessing the participant's pain due to OA in the target knee. Each question was scored on an NRS scale from 0 to 10, and the WOMAC pain subscale score is calculated as the mean score from all 5 questions, where higher scores represent higher pain. Change from baseline in WOMAC pain subscale to Weeks 2, 4,6, 8, 10, and 18 is reported.
Change From Baseline in WOMAC PF Subscale Over Time	Baseline (Week 0; Day 1), Weeks 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), and 18 (Day 126)	The WOMAC multiscale index is used to assess pain, stiffness, and joint functionality in the past 48 hours in participants with OA of the knee or hip. The WOMAC PF subscale consists of 17 questions assessing the participant's difficulty in performing activities of daily living due to OA in the target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC PF subscale score is calculated as the mean score from all 17 questions, where higher scores represent worse function. Change from baseline in WOMAC physical function to Weeks 2, 4, 6, 8, 10, and 18 is reported.
Change From Baseline in WOMAC Overall Score Over Time	Baseline (Week 0; Day 1), Weeks 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), 12 (Day 84), and 18 (Day 126)	The WOMAC overall score consisted of all 24 questions reported in the WOMAC questionnaire to assess: i) pain subscale, ii) PF subscale and iii) stiffness subscale. WOMAC overall score was calculated as the mean score from all 24 questions each scored on a Likert scale from 0 to 10 where higher scores represent worse outcome. Change from baseline in weekly average of WOMAC overall score to Weeks 2, 4, 6, 8, 10, 12, and 18 is reported.
Change From Baseline in WOMAC Stiffness Scores Over Time	Baseline (Week 0; Day 1), Weeks 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), 12 (Day 84), and 18 (Day 126)	The WOMAC stiffness function subscale consists of 2 questions assessing stiffness due to OA in the target knee. Stiffness is defined as a sensation of decreased ease of movement in the target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC stiffness function subscale score is calculated as the mean score from the 2 questions, where higher scores represent higher stiffness. Change from baseline in WOMAC stiffness score to Weeks 2, 4, 6, 8, 10, 12, and 18 is reported.
Change From Baseline in PGA of OA Over Time	Baseline, Weeks 2 (Day 14), 4 (Day 28), 8 (Day 56), 10 (Day 70), and 18 (Day 126)	The PGA of OA was a 5-point Likert scale used to assess symptoms and activity impairment due to OA of the knee. Participants were asked to identify a number from 1 = "very good (asymptomatic and no limitation to normal activities)" to 5 = "very poor (very severe symptoms which are intolerable and inability to carry out all normal activities)" based on the question "Considering all the ways that OA of the knee affects you, how are you feeling today?". Change from baseline in PGA of OA to Weeks 2, 4, 8, 10, and 18 is reported.
Percentage of Participants With Improvement of >= 2 Points in PGA of OA	Weeks 2 (Day 14), 4 (Day 28), 8 (Day 56), 12 (Day 84), and 18 (Day 126)	The PGA of OA was a 5-point Likert scale used to assess symptoms and activity impairment due to OA of the knee. Participants were asked to identify a number from 1 = "very good (asymptomatic and no limitation to normal activities)" to 5 = "very poor (very severe symptoms which are intolerable and inability to carry out all normal activities)" based on the question "Considering all the ways that OA of the knee affects you, how are you feeling today?". Percentage of participants with improvement of \>= 2 points in PGA of OA at Weeks 2, 4, 8, 12, and 18 is reported.
Percentage of Participants With >= 30% and >= 50% Reductions in Weekly Average of Daily NRS Pain Score Over Time	Baseline (Day -7 to Day -1, inclusive), Weeks 2 (Day 14), 4 (Day 28), 8 (Day 56), 12 (Day 84), and 18 (Day 126)	The NRS is an 11-point Likert scale used to assess pain, where participants were asked to describe their average pain in the target knee by identifying a number from 0 = "no pain" to 10 = "most severe pain imaginable over the previous 24 hours". This will be recorded on a daily basis at approximately the same time every morning via ePRO diary. Percentage of participants with \>= 30% and \>= 50% reductions in weekly average of daily NRS pain score are reported.
Percentage of Participants With >= 30% and >= 50% Reductions in WOMAC Physical Function Subscale Over Time	Baseline (Week 0; Day 1), Weeks 2 (Day 14), 4 (Day 28), 8 (Day 56), 12 (Day 84), and 18 (Day 126)	The WOMAC PF subscale consists of 17 questions assessing the participant's difficulty in performing activities of daily living due to OA in the target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC PF subscale score is calculated as the mean score from all 17 questions, where higher scores represent worse function. Percentage of participants with \>= 30% and \>= 50% reductions in WOMAC physical function subscale over time are reported.
Serum Concentration of MEDI7352	Baseline (Day 1), Day 7; pre-dose on Days 14, 28, 42, 56, and 70; and on Days 74, 77, 84, 126, and 224	Serum concentration of MEDI7352 is reported.
ADA Titre in Participants Who Were ADA Positive at Baseline and/or Post-baseline	Baseline (Day 1), Day 7; pre-dose on Days 14, 28, 42, 56, and 70; and on Days 74, 77, 84, 126, and 224	The ADA titre in participants who were ADA positive at baseline and/or post-baseline is reported.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	Day 1 through 41 weeks (maximum observed duration)	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Clinically Significant Findings in Physical Examination Reported as TEAEs	Day 1 through 41 weeks (maximum observed duration)	Number of participants with clinically significant findings in physical examination reported as TEAE are reported. A physical examination included assessments of general appearance, skin, head and neck, examination of the oral cavity for any lesions, lymph nodes, thyroid, abdomen (bowel sounds, liver, and spleen palpation), back (including costovertebral angle tenderness), musculoskeletal/extremities, cardiovascular, and respiratory systems.
Total Neuropathy Score-Nurse (TNSn) Over Time	Baseline (Day -45 to Day -1), Weeks 0 (Day 1), 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), 12 (Day 84), 28 (Day 196), and 32 (Day 224)	The TNSn, is a semiquantitative clinical assessment of peripheral nervous system function. The TNSn assessment is collected as scores of motor symptom, autonomic symptom, pin sensibility, sensory symptom, and vibration sensibility score. Each neuropathy item is scored on a 0 to 4 scale with total score ranging from 0 to 20. Higher total scores correlate with more severe neuropathy.
Number of Participants With Abnormal Vital Signs Reported as TEAEs	Day 1 through 41 weeks (maximum observed duration)	Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormalfinding in the vital sign parameters (body temperature, supine and standing blood pressure, pulse rate, and respiratory rate).
Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)	Weeks 0 (Day 1), 2 (Day 14), 4 (Day 28), 8 (Day 56), 10 (Day 70), 12 (Day 84), 28 (Day 168), and 32 (Day 224)	Number of participants with clinically significant abnormal ECGs are reported.
Percentage of Responder Participants Measured by Osteoarthritis Research Society International (OARSI) Responder Index Using Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) Definition	Weeks 2 (Day 14), 4 (Day 28), 8 (Day 56), 12 (Day 84), and 18 (Day 126)	The OMERACT-OARSI responder index is calculated from the WOMAC Pain subscale, the WOMAC Physical Function Subscale and the PGA of OA. A participant is classified as a responder if: 1. \>= 2-point absolute change from Baseline to Week X or a \>= 50% improvement is reported in the WOMAC Pain or the PF subscales; 2. At least 2 of the following 3 conditions are true: \>= 1-point absolute change from Baseline to Week X or \>= 20% improvement is reported in the WOMAC Pain subscale, \>= 1-point absolute change from Baseline to Week X or \>= 20% improvement is reported in the WOMAC PF subscale or \>= 1-point absolute change from Baseline to Week X is reported in the PGA of OA. Percentage of responder participants are reported.
Change From Baseline in Weekly Average of Daily NRS Pain Score Over Time	Baseline (Day -7 to Day -1, inclusive), Weeks 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), and 18 (Day 126)	The NRS is an 11-point Likert scale used to assess pain, where participants were asked to describe their average pain in the target knee by identifying a number from 0 = "no pain" to 10 = "most severe pain imaginable over the previous 24 hours". This will be recorded on a daily basis at approximately the same time every morning via ePRO diary. Change from baseline in weekly average of daily NRS to Weeks 2, 4, 6, 8, 10, and 18 is reported.
Percentage of Participants With >= 30% and >= 50% Reductions in WOMAC Pain Subscale Score Over Time	Baseline (Week 0; Day 1), Weeks 2 (Day 14), 4 (Day 28), 8 (Day 56), 12 (Day 84), and 18 (Day 126)	The WOMAC multiscale index is used to assess pain, stiffness, and joint functionality in the past 48 hours in participants with OA of the knee or hip. The WOMAC pain subscale consists of 5 questions assessing the participant's pain due to OA in the target knee. Each question was scored on an NRS scale from 0 to 10, and the WOMAC pain subscale score is calculated as the mean score from all 5 questions, where higher scores represent higher pain. Percentage of participants with \>= 30% and \>= 50% reductions in WOMAC pain subscale score over time are reported.
Number of Participants With Positive Anti-Drug Antibodies (ADA) to MEDI7352	Baseline (Day 1), Day 7; pre-dose on Days 14, 28, 42, 56, and 70; and on Days 74, 77, 84, 126, and 224	Number of participants with ADA to MEDI7352 are reported. Treatment-induced ADA positive is defined as ADA negative at baseline and positive at least 1 post-baseline ADA assessment. Treatment-boosted ADA positive is defined as ADA positive at baseline, and the baseline titre is boosted by greater than the variability of the assay (commonly 4-fold) at \>= 1 post-baseline timepoint. Persistent positive is defined as ADA negative at baseline and having at least 2 post-baseline ADA positive assessments (with \>= 16 weeks between first and last positive) or ADA positive at last post-baseline assessment. Transiently positive is defined as ADA negative at baseline and at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.
Number of Participants With Clinically Significant Abnormal Findings in Neurological Examination	Baseline (Day -45 to Day -1), Weeks 0 (Day 1), 2 (Day 14), 4 (Day 28), 6 (Day 42), 8 (Day 56), 10 (Day 70), 12 (Day 84), 18 (Day 126), 28 (Day 168), 32 (Day 224), and 36 (Day 252)	Number of participants with clinically significant abnormal findings in neurological examination is reported. The neurological examination included assessment of mental status, cranial nerves, motor examination (muscle strength and tone), upper and lower extremity deep tendon reflexes, plantar responses, sensory system examination, coordination, and gait.
Change From Baseline in Weight (kg) to Week 12	Baseline (Day -45 to -1) and Week 12	Change from baseline in weight (kg) to Week 12 is reported.
Change From Baseline in Survey of Autonomic Symptoms (SAS) Total Impact Score	Baseline (Day 1; Week 0) and Day 252 (Week 36)	The SAS is an instrument that measures autonomic symptoms used for assessing autonomic neuropathies in clinical trials. The SAS scale evaluates the presence of symptoms and the degree of severity. The SAS consists of 11 questions in women and 12 questions in men. Each question has a Yes or No answer to symptoms occurring 6 months prior to investigational product (IP) administration. Questions answered with "Yes" are further rated by asking the participant how much each symptom is bothering him or her. Each answer is scored on a scale from 1 to 5 where 1 = not at all and 5 = a lot, and a total symptom impact score is determined. The SAS total impact score is the total of the scores from each question (11 for women and 12 for men). The minimum score is 0 and the maximum is 55 for women and 60 for men. A higher score indicates worse autonomic dysfunction.
Number of Participants With Injection Site Reactions	Day 1 through 41 weeks (maximum observed duration)	Number of participants with injection site reactions are reported.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	Day 1 through 41 weeks (maximum observed duration)	Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.
Change From Baseline in C-reactive Protein Level to Week 12	Baseline (Day -7 to -1, inclusive) and Week 12	Change from baseline in C-reactive protein level to Week 12 is reported.
Number of Participants With Abnormal X-ray and/or Magnetic Resonance Imaging (MRI) of Large Joints	Baseline (Day -45 to -1) and Week 32	Number of participants with abnormal X-ray and/or MRI of large joints is reported.