A Multi-part, Phase I/II Study to Evaluate the Safety and Tolerability of GRWD0715 in Healthy Human Volunteers and Participants With Axial Spondyloarthritis
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 140
- 试验地点
- 22
- 主要终点
- Incidence and nature of dose limiting event(s) (DLE)s (Parts A and B only)
研究概览
简要总结
GRWD0715 is an orally administered, selective inhibitor of the Endoplasmic Reticulum Aminopeptidase 1 [ERAP1] enzyme being explored as a potential new treatment for axial spondyloarthritis (axSpA), a long term condition caused by inflammation predominantly affecting the sacroiliac joints (SIJs) and spine.
详细描述
GRWD0715 is an orally administered, selective inhibitor of the Endoplasmic Reticulum Aminopeptidase 1 [ERAP1] enzyme being explored as a potential new treatment for axial spondyloarthritis (axSpA), a long term condition caused by inflammation predominantly affecting the sacroiliac joints (SIJs) and spine.
ERAP1 is involved in trimming antigens from foreign bodies (e.g. bacteria, viruses) which are presented on the surface of a cell to trigger an immune response. In axSpA, it is thought an antigen from the person's own body, called a 'self-peptide' is presented by the ERAP1 processing pathway and incorrectly recognised by the immune system. The hypothesis is that stimulation of the immune system by the presentation of this self-peptide causes the inflammatory symptoms experienced by people living with axSpA.
As an inhibitor of ERAP1, GRWD0715 aims to prevent the generation of the antigenic self-peptide, and thus remove the stimulus of the immune system. If the immune system is not activated, the immune attack on the sacroiliac joint (SIJ) and spine would stop, halting the axSpA disease progress.
The study will consist of 4 parts: Part A conducted in healthy human volunteers, and Part B, Part C and/or D in participants with axSpA. The primary goal of Parts A, B and C is to assess whether GRWD0715 is safe and well tolerated in healthy human volunteers and participants with axSpA. The primary goal of Part D is to review whether GRWD0715 is efficacious when compared to placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Parts A, B, and C - None (Open Label). Part D will be double-blind
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Healthy Volunteers
- •Healthy male and female subjects aged 18-55 years inclusive, at the Screening visit
- •Participant must provide written informed consent to participate in the study
- •Participant must be able and willing to comply with the requirements of the protocol (including dietary restrictions and exclusion of grapefruit juice)
- •Male participants (and their female partners) / female participants must be willing to adhere to contraception requirements as detailed in the protocol
- •Non-smokers or ex-smokers who have not smoked within the previous 6 months, as determined at the Screening visit
- •Participant with a Body Mass Index (BMI) of 19-
- •Body Mass Index = Body weight (kg) / [Height (m)]2 AxSpA Participants
- •Male or female, 18-65 years of age
- •Participants diagnosed with Axial Spondyloarthritis, also fulfilling ASAS classification criteria including:
- •HLA-B27 +ve (local testing)
- •Objective evidence of inflammation at screening, defined as active sacroiliac joint inflammation on MRI fulfilling the ASAS MRI criteria (MRI+), assessed by the Principal Investigator or appropriately trained delegate, and/or elevated C-reactive protein (CRP+) ≥5.0mg/L.
- •o Objective evidence of inflammation may not be required for Part B. Participants who do not require objective evidence of inflammation require Sponsor approval prior to screening for and/or enrolling to the study.
- •A score of:
- •≥ 2.1 (High Disease Activity) on the Ankylosing Spondylitis Disease Activity Score (ASDAS) on current treatment* OR
- •In Part B only, A: a score of >1.3 (Low to Moderate Disease Activity) on the ASDAS on current treatment. Participants with a score of ≥1.3 and < 2.1 require Sponsor approval prior to screening for the study.
- •At least one of the following:
- •Current treatment with a NSAID, at a n adequate dose and duration per local clinical guidelines, with inadequate clinical response OR
- •Intolerance to ≥1 NSAID or contraindication(s) to NSAIDs
- •Participants may have received 1 or 2 (Australia only) prior b/tsDMARD and discontinued due to intolerance or inadequate efficacy provided that:
- •Part B: Participants who have received two prior b/ts DMARDs require Sponsor approval prior to screening.
- •Part D: Participants with prior b/tsDMARD treatment may be capped.
- •Participants who have received 1/(Australia only) 2 prior treatments are required to undergo a washout at minimum: Biologic DMARDs 4 weeks or 5 half-lives prior to Day 1, whichever is longer. Any JAK inhibitor DMARDs 2 weeks prior to Day 1
- •Part C only: Participants enrolling into Part C must:
- •Have completed Part B or Part D treatment per protocol.
- •Have not permanently discontinued GRWD0715 due to safety concerns.
- •Have no ongoing safety issues that, in the opinion of the Investigator, would preclude further treatment.
- •Provide written informed consent to participate in Part C.
- •Part D only: Participants must be GRWD0715 naïve.
- •Contacts/Locations Central Contact Person: Grey Wolf Therapeutics Patient enquiries Telephone: +44 1235644970
排除标准
- •Healthy Volunteers
- •History or presence of any clinically significant findings in medical history, physical examination, vital signs and/or laboratory tests that, in the opinion of the Investigator, would preclude inclusion in the study
- •Participation in a New Chemical Entity clinical study within the previous 124 days or a marketed drug clinical study within the previous 93 days
- •Known infection or lifestyle risk factors for human immunodeficiency virus (HIV) and/or hepatitis B or C infection, as determined at the Screening visit AxSpA Participants
- •Parts B and D only: Participants previously treated with three or more b/tsDMARDs
- •Participants not meeting inclusion criteria for prior b/tsDMARD exposure or required washout period for their respective study part.
- •Participants currently receiving prohibited conventional DMARDS cDMARDS), thalidomide (including previous use) or other prohibited concomitant medications.
- •Inadequate Haematologic function, defined as:
- •Haemoglobin <10 g/dL.
- •Absolute white blood cell count <3.0 x 10^9 /L (<3000 mm^3)
- •Absolute neutrophil count <1.2 x 10^9 /L (<1200 mm^3)
- •Absolute lymphocyte count <1.0 x 10^9 /L (<1000 mm^3)
- •Platelet count <100 x 10^9 /L (<100.000 mm^3)
- •Inadequate liver function, defined as; total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal at screening visit. For subjects with Gilberts syndrome, upper limit of normal for total bilirubin will be 2.9mg/dl
- •History of any other autoimmune rheumatic disease (e.g., psoriatic arthropathy, systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymositis) or known diagnosis of fibromyalgia
- •Participants with a previous history of or currently stable psoriasis are eligible
- •Active or symptomatic inflammatory bowel disease (IBD). Participants with a history of IBD are allowed to participate
- •Presence of active anterior uveitis
研究组 & 干预措施
Part D - Randomised, placebo-controlled, expansion cohort in participants with axSpA
Part D - Randomised expansion cohort of GRWD0715 vs. placebo
Depending on the data from Part B, and the availability of one or more biologically active doses that are safe and well tolerated, participants will be randomised to receive either one or two dose levels of GRWD0715, or placebo to match (PTM). If one dose level is selected, participants will be randomised in a 4:1 ratio (GRWD0715:PTM).
If two dose levels are selected, participants will be randomised in a 2:2:1 ratio (two GRWD0715 dose arms and PTM). Treatment will be administered once daily for up to 12 weeks.
干预措施: Part D - Randomised, placebo-controlled, expansion cohort in participants with axSpA (Drug)
Part A - Single Ascending Dose (SAD) in Healthy Human Volunteers
Drug: Part A - Single Ascending Dose (SAD) of GRWD0715 Participants in Part A will receive a single dose of GRWD0715 on Day 1 only.
干预措施: Part A - Single Ascending Dose (SAD) in Healthy Human Volunteers (Drug)
Part C - Safety expansion cohort participants with axSpA
Participants who previously completed Part B and OR randomized to the placebo arm in Part D:
Part C - Open-label safety expansion cohort with GRWD0715 Participants from Part B or Part D of the study will be permitted to participate in Part C will receive GRWD0715 for 8 or 12 weeks, respectively.Immediate rollovers from Part B: If Part C is open while a Part B cohort is enrolling, participants may roll over directly into Part C without a washout period and continue treatment at their current assigned dose level of GRWD0715 from Part B, once daily, for an additional 8 weeks.
Returning rollovers from Part B: If Part C is open, participants from previously completed Part B cohorts may return to enrol in Part C at the Part B dose currently reviewed and approved by the Safety Review Committee at the time of their return, once daily, for up to an additional 8 weeks.
Placebo Rollovers from Part D: will receive 12 weeks of open-label, daily dosing with GRWD0715 in Part C
干预措施: Part C - Safety expansion cohort in participants with axSpA (Drug)
Part B - Multiple Ascending Dose (MAD) in participants with axSpA
Drug: Part B - Multiple Ascending Dose (MAD) of GRWD0715 Participants in Part B will receive GRWD0715 for 28 days
干预措施: Part B - Multiple Ascending Dose (MAD) in participants with axSpA (Drug)
结局指标
主要结局
Incidence and nature of dose limiting event(s) (DLE)s (Parts A and B only)
时间窗: From first dose to 15 days post last dose of study drug
To determine safety and tolerability of GRWD0715 in healthy volunteers (Part A) and participants with axSpA (Part B)
Analysis of SPARCC MRI activity of the SIJs (sacroiliac joints) and spine
时间窗: From baseline/Day 1 to Week 12
To determine the efficacy of GRWD0715 compared to placebo in participants with axSpA (Part D)
Incidence and nature of dose limiting event(s) (DLE)s (Parts A and B only)
时间窗: From first dose to 15 days post last dose of study drug
To determine safety and tolerability of GRWD0715 in healthy volunteers (Part A) and participants with axSpA (Part B)
Incidence, Type and Severity of treatment related adverse events (TRAEs)
时间窗: From first dose to 15 days post last dose of study drug
To determine safety and tolerability of GRWD0715 in healthy volunteers (Part A) and participants with axSpA (Parts B and C)
Analysis of SPARCC MRI activity of the SIJs (sacroiliac joints) and spine
时间窗: From baseline/Day 1 to Week 12
To determine the efficacy of GRWD0715 compared to placebo in participants with axSpA (Part D)
Incidence, type and severity of treatment emergent adverse events (TEAEs)
时间窗: From first dose to 15 days post last dose of study drug
To determine safety and tolerability of GRWD0715 in healthy volunteers (Part A) and participants with axSpA (Parts B and C)
To determine the efficacy of GRWD0715 compared to placebo in participants with axSpA (Part D)
时间窗: From baseline/Day 1 to Week 12
Analysis of the Assessment of Spondyloarthritis International Society (ASAS) Core Outcome Set (COS). ASAS20 (improvement of 20% or more and 1 unit or more; improvement in at least 3 of 4 domains; no worsening on fourth dimension) and ASAS40 (improvement of 40% and 2 units or more; improvement in at least 3 of 4 domains; no worsening on fourth dimension) will be calculated from constituent questions with the ASAS COS clinical measures and patient reported outcomes
Parts A, B and C: Incidence of treatment emergent (TEAE) and treatment related adverse events (TRAEs)
时间窗: Immediately after the first dose of GRWD0715 through to study completion after 4-12 weeks.
Any adverse event AE reported or observed after the start of dosing with any study treatment until completion of the last study related procedure (includes follow-up for safety assessments) will be recorded as a treatment-emergent AE (TEAE). If the TEAE is considered related to the study drug as per the definitions of relatedness listed in ('possibly', 'probably' or 'definitely' related) it will be considered a treatment-related AE (TRAE).
Parts A and B: Incidence and nature of dose limiting events (DLEs).
时间窗: Part A: the DLE period will be 15 Days from the start of dosing Part B: the DLE period will be 35 days from the start of dosing
DLEs are on Grade 2 (moderate) events that are classified as related to study drug and are not resolved within 7 days. Any Grade 2 events lasting longer than 7 days, events of a higher grade, events that require study drug discontinuation or which meet the criteria for Seriousness and are related to study drug are counted as DLEs.
Analysis of clinical response per Assessment of SpondyloArthritis International Society (ASAS) core outcome set compared to placebo. Higher scores mean worse outcome: Continuous Calculated Scores
时间窗: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
The ASAS core outcome set (COS) will be conducted in participants and includes the following questionnaires which use Continuous Calculated Scores: Ankylosing Spondylitis Disease Activity Score (ASDAS)- A specific mathematically weighted index that combines patient-reported outcomes and blood inflammatory markers. Bath Ankylosing Spondylitis Function Index (BASFI) - A mean score derived from 10 individual visual/numeric questions regarding physical function. Assessment of SpondyloArthritis (ASAS) Health Index - A composite health and functioning score calculated from a specific 17-item questionnaire.
Analysis of clinical response per Assessment of SpondyloArthritis International Society (ASAS) core outcome set compared to placebo. Higher scores mean worse outcome: Numeric Rating Scales
时间窗: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
The ASAS core outcome set (COS) will be conducted in participants and includes the following questionnaires which use numeric rating scales (0-10): NRS Patient Global Assessment of Disease Activity (PGA-DA): A single 0-10 scale rating overall disease impact. NRS total back pain (BASDAI Q2): A single 0-10 scale rating spinal pain. NRS fatigue (BASDAI Q1): A single 0-10 scale rating tiredness levels. NRS average duration and severity of morning stiffness (BASDAI \[Q5+Q6\]/2): An average calculation derived from two separate 0-10 numeric rating scales.
Analysis of clinical response per Assessment of SpondyloArthritis International Society (ASAS) core outcome set compared to placebo. Higher scores mean worse outcome: Direct Anatomical Counts
时间窗: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
The ASAS core outcome set (COS) will be conducted in participants and includes the following assessments which use direct anatomical counts: 44 swollen joint count (Part D): A literal tally of how many joints out of 44 are actively swollen. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) (Part D only): A tally of painful areas out of 13 specific enthesitic insertion sites. Dactylitis count: A literal tally of the number of digits (fingers and toes) exhibiting uniform swelling (Part D only) ASAS20 and ASAS 40 scores will be calculated from constituent questions within the ASAS COS clinical outcome measures and patient reported outcome measures.
Analysis of clinical response per SPARCC MRI (magnetic resonance imaging) Activity of the sacroiliac joints and spine in the core outcome set compared to placebo
时间窗: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
The SPARCC Scoring System measures active inflammation and structural joint damage in the sacroiliac joints using MRI, through the following: Inflammation Scoring (Bone Marrow Edema): Slice selection: Evaluates six consecutive, specialized coronal MRI slices through the joint. Joint quadrants: Divides each sacroiliac joint into four distinct quadrants (upper and lower iliac, upper and lower sacral). Basic scoring: Gives 1 point for the presence of bone marrow edema in each quadrant. Intensity and depth bonuses: Adds extra points for lesions that show very high signal intensity or great depth (\>1 cm). Maximum score: Reaches a total high score of 72 points for inflammation Structural Damage Scoring: Erosions: Measures loss of bone at the joint surface. Fat lesions: Tracks areas where bone marrow is replaced by fat. Backfill and ankylosis: Detects tissue repair and joint fusion
次要结局
- PK Parameter T1/2 (Half life)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- Analysis of SPARCC MRI activity of the SIJs (sacroiliac joints) and spine(From baseline/Day 1 to Week 12)
- Incidence, Type and Severity of treatment related adverse events (TRAEs)(From first dose to 15 days post last dose of study drug)
- Incidence, type and severity of treatment emergent adverse events (TEAEs)(From first dose to 15 days post last dose of study drug)
- PK Parameter Tmax (Time to maximum observed concentration)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- PK Parameter AUC0-t (Area under the concentration-time curve)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- PK Parameter AUC0-t (Area under the concentration-time curve)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- PK Parameter T1/2 (Half life)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- To assess the preliminary efficacy of GRWD0715 (Part C)(From baseline/Day 1 to Week 12)
- Analysis of SPARCC MRI activity of the SIJs (sacroiliac joints) and spine(From baseline/Day 1 to Week 12)
- Incidence, Type and Severity of treatment related adverse events (TRAEs)(From first dose to 15 days post last dose of study drug)
- PK Parameter Trough Concentrations(From Day 1 to Day 4 (Part A) / Day 35 (Part B) / Week 12 (Parts C and D))
- PK Parameter Tmax (Time to maximum observed concentration)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- Incidence, type and severity of treatment emergent adverse events (TEAEs)(From first dose to 15 days post last dose of study drug)
- PK Parameter Cmax (Maximum observed concentration)(From Day 1 to Day 4 (Part A) / Day 35 (Part B))
- Parts A, B and C: PK - trough concentrations (Cmin)(Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8)
- Parts A, B and C: PK - maximum observed concentration (Cmax)(Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8)
- Parts A, B and C: PK - time to Cmax (Tmax)(Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8)
- Parts A, B and C: PK - area under the concentration-time curve (AUC0-t)(Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8)
- Parts A, B and C: PK - half-life (t1/2)(Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8)
- Part B: A Biologically Active Dose (BAD) will be identified(The Biologically Active Dose will be assessed every 3 months in Part B on the completion of each of the 6 dose cohorts for up to a total of 14 months.)
- Parts A, B and C: Maximum tolerated dose (MTD): the MTD will be determined by the incidence of DLEs according to the MTD evaluation process.(MTD will be assessed on the completion of each dose level cohort.)