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A Trial to Evaluate the Safety and Tolerability of Namilumab (MT203) in Patients With Mild to Moderate Rheumatoid Arthritis (PRIORA)

Primary Purpose

Rheumatoid Arthritis

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
namilumab (MT203)
Placebo
Sponsored by
Takeda
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Rheumatoid Arthritis, MT203, Human IgG1 monoclonal antibody, GM-CSF monoclonal antibody

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Out-patients with active rheumatoid arthritis (RA), according to the ACR 1987 revised criteria, with low to moderate disease activity (DAS28-ESR ≥ 2.6 and ≤ 5.1)
  2. Patients must be on stable doses of methotrexate (MTX) ≥ 7.5 and ≤ 25 mg/week for at least 12 weeks before the first injection, with appropriate folic acid supplementation
  3. Age ≥ 18 years at Screening
  4. Body weight at least 50 kg at Screening; BMI: ≥ 18.0 and ≤ 30.0 kg/m2 at Screening
  5. Negative tuberculosis test at Screening
  6. Heterosexually active male and female patients of childbearing potential are obliged to follow whatever contraceptive and / or breastfeeding restrictions may be required for their concomitant medication(s), including methotrexate.

In addition, heterosexually active male and female patients of childbearing potential are required to use effective double-method contraception (one hormonal contraceptive or intrauterine device and one other additional contraceptive method) for 1 month before the first administration of the IMP, during the course of the trial, and for 6 month after the last injection of MT203.

No special requirements are made for female patients proven to be post-menopausal (at least 2 years after last menstrual period and FSH ≥ 40IU/L), surgically sterilized or hysterectomized. Likewise no special requirements for heterosexually active male who are surgical sterilized.

Pregnant or lactating female patients have to be excluded.

Exclusion Criteria:

  1. Participation in another clinical trial or previous dosing in this trial
  2. Use of specified medications within certain timeframes or use of certain comedications
  3. History or presence of specified diseases
  4. Drug abuse
  5. Certain laboratory parameters outside a specified range
  6. Donation of blood
  7. Relevant decrease in lung function
  8. Infections, frequent or chronic infections, herpes zoster
  9. Females: positive pregnancy test
  10. Presence of history of tuberculosis
  11. History of malignancy

Sites / Locations

  • Nycomed Investigational Site
  • Nycomed Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Namilumab 150 mg

Namilumab 300 mg

Placebo

Arm Description

Namilumab (MT203) 150 mg (low dose), subcutaneous (SC) injection, on Days 1, 15 and 29.

Namilumab (MT203) 300 mg (high dose), SC injection, on Days 1, 15 and 29.

Namilumab-matching placebo, SC injection, on Days 1, 15 and 29.

Outcomes

Primary Outcome Measures

Number of Participants With Clinically Significant Clinical Laboratory Results
Blood was collected for Haematology, Chemistry and Coagulation. Urine was collected for Urinalysis. Alert values for laboratory results include the following: Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl-transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin (TBil): > 3 times upper limit of normal (ULN). Creatinine and Glucose: > 2 times ULN. Potassium > 6.0 or < 3.0 mmol/L. Haemoglobin: Male < 8.0 ;Female < 7.0 g/dL. Erythrocytes :Male < 3.5 x 10^12/L or > 7 x 10^12/L;Female < 3.0 x 10^12/L or > 6.5 x 10^12/L. White Blood Cells (WBC): < 2.8 x10^9/L or > 16.0 x 10^9/L. Eosinophils > 20 % of cells in the WBC differential. Platelet Count < 75 x 10^9/L or 600 x 10^9/L. No alert values were identified for Coagulation or Urinalysis.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
Alert values for ECG were: Heart rate < 35 bpm or > 120 bpm, QTc acc. to Bazett (absolute value)> 500 ms or QTc acc. to Bazett (increase versus Baseline (pre-treatment).
Number of Participants With Clinically Significant Vital Signs
Vital signs included Systolic Blood Pressure (BP), Diastolic BP, body temperature, heart rate. Alert values were: BP systolic > 170 mmHg or < 85 mmHg, BP diastolic > 105 mmHg, Difference BP systolic vs. Baseline (pre-treatment) > 40 mmHg or Pulse rate < 35 bpm or > 120 beats per minute (bpm).
Number of Participants With Clinically Significant Pulmonary Function Tests
Pulmonary function was determined by forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak flow.
Number of Participants With Clinically Significant Physical Examination Findings
The physical examination included body system assessments: eyes, head and neck (including thyroid), ears, nose and throat, lymph nodes, cardiovascular, lungs, mammae, abdomen (liver, spleen), genitals, limbs, central and peripheral nervous system, musculoskeletal system, skin & nails, mucosae. The Investigator classified abnormal findings as either clinically significant or not clinically significant.
Number of Participants Reporting One or More Treatment Emergent Adverse Events
An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Secondary Outcome Measures

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MT203
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax
Cmax: Maximum Observed Plasma Concentration for MT203
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MT203
AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]).
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MT203
AUC(0-inf) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau]), where tau is the length of the dosing interval in this study).
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MT203
Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.
Terminal Phase Elimination Half-life (T1/2) for MT203
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Ctrough: Maximum Observed Plasma Concentration Pre-Dose
Change From Baseline in Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Plasma
MT203/GM-CSF complexes were analysed using a procedure that quantified GM-CSF after dissociation from the complex. The determined concentrations corresponded to the amount of total (free and complexed) GM-CSF in the plasma sample. A positive change from Baseline indicated improvement.
Change From Baseline in MT203/GM-CSF Complexes in Plasma
MT203/GM-CSF complexes were analysed using a procedure that quantified GM-CSF after dissociation from the complex. The determined concentrations corresponded to the amount of total (free and complexed) GM-CSF in the plasma sample. A positive change from Baseline indicated improvement.
Number of Participants With Anti-MT203 Antibodies
Serum samples were tested for the presence of anti-MT203 antibodies by a bridging Electro-chemi-luminescent assay (ECL-assay).
Percentage of Participants With American College of Rheumatology (ACR 20) Response
ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant Erythrocyte Sedimentation Rate.
Change From Baseline in the Disease Activity Score 44-Erythrocyte Sedimentation Rate (DAS44-ESR)
Ritchie articular index (RAI); a joint count that grades the tenderness of 26 joints on a scale of 0-3); the number of swollen joints from 44 joints (swollen44); ESR in mm/hour after 1 hour and the patient's global disease activity on a Visual Analogue Scale (VAS) of 100 mm (0=no disease activity to right end of the line 100=maximum disease activity) were used to calculate DAS44-ESR using the following formula: DAS44-ESR = 0.54*sqrt(RAI) + 0.065*(swollen44) + 0.33*ln(ESR) + 0.0072*VAS. Lower numbers were better. A negative change from Baseline indicated improvement.

Full Information

First Posted
February 18, 2011
Last Updated
July 24, 2015
Sponsor
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT01317797
Brief Title
A Trial to Evaluate the Safety and Tolerability of Namilumab (MT203) in Patients With Mild to Moderate Rheumatoid Arthritis
Acronym
PRIORA
Official Title
A Phase Ib Double-blind, Placebo-controlled, Randomized, Dose-escalating Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Repeated Subcutaneous Injections of MT203 in Patients With Mild to Moderate Rheumatoid Arthritis on Treatment With Methotrexate
Study Type
Interventional

2. Study Status

Record Verification Date
July 2015
Overall Recruitment Status
Completed
Study Start Date
March 2011 (undefined)
Primary Completion Date
August 2013 (Actual)
Study Completion Date
August 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Takeda

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this trial is primarily to investigate the safety and tolerability of repeated subcutaneous injections of MT203 in patients with mild to moderate rheumatoid arthritis. Furthermore, the amount of MT203 in the blood will be measured and it will be investigated how the body responds to MT203 treatment and if MT203 is effective in the treatment of rheumatoid arthritis.
Detailed Description
The trial medication will be administered at 2 dose levels as subcutaneous injections. Each patient will receive three injections in total. The trial duration consists of a screening period (28 - 2 days prior to the first injection) and a treatment and observation period (4 months). The trial requires approximately 20 visits at the study site.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
Keywords
Rheumatoid Arthritis, MT203, Human IgG1 monoclonal antibody, GM-CSF monoclonal antibody

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Namilumab 150 mg
Arm Type
Experimental
Arm Description
Namilumab (MT203) 150 mg (low dose), subcutaneous (SC) injection, on Days 1, 15 and 29.
Arm Title
Namilumab 300 mg
Arm Type
Experimental
Arm Description
Namilumab (MT203) 300 mg (high dose), SC injection, on Days 1, 15 and 29.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Namilumab-matching placebo, SC injection, on Days 1, 15 and 29.
Intervention Type
Drug
Intervention Name(s)
namilumab (MT203)
Intervention Description
administered three times, subcutaneous in the abdomen
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
administered three times, subcutaneous in the abdomen
Primary Outcome Measure Information:
Title
Number of Participants With Clinically Significant Clinical Laboratory Results
Description
Blood was collected for Haematology, Chemistry and Coagulation. Urine was collected for Urinalysis. Alert values for laboratory results include the following: Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl-transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin (TBil): > 3 times upper limit of normal (ULN). Creatinine and Glucose: > 2 times ULN. Potassium > 6.0 or < 3.0 mmol/L. Haemoglobin: Male < 8.0 ;Female < 7.0 g/dL. Erythrocytes :Male < 3.5 x 10^12/L or > 7 x 10^12/L;Female < 3.0 x 10^12/L or > 6.5 x 10^12/L. White Blood Cells (WBC): < 2.8 x10^9/L or > 16.0 x 10^9/L. Eosinophils > 20 % of cells in the WBC differential. Platelet Count < 75 x 10^9/L or 600 x 10^9/L. No alert values were identified for Coagulation or Urinalysis.
Time Frame
From Day 1 Up to Day 118
Title
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
Description
Alert values for ECG were: Heart rate < 35 bpm or > 120 bpm, QTc acc. to Bazett (absolute value)> 500 ms or QTc acc. to Bazett (increase versus Baseline (pre-treatment).
Time Frame
From Day 1 Up to Day 118
Title
Number of Participants With Clinically Significant Vital Signs
Description
Vital signs included Systolic Blood Pressure (BP), Diastolic BP, body temperature, heart rate. Alert values were: BP systolic > 170 mmHg or < 85 mmHg, BP diastolic > 105 mmHg, Difference BP systolic vs. Baseline (pre-treatment) > 40 mmHg or Pulse rate < 35 bpm or > 120 beats per minute (bpm).
Time Frame
From Day 1 Up to Day 118
Title
Number of Participants With Clinically Significant Pulmonary Function Tests
Description
Pulmonary function was determined by forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak flow.
Time Frame
From Day 1 Up to Day 118
Title
Number of Participants With Clinically Significant Physical Examination Findings
Description
The physical examination included body system assessments: eyes, head and neck (including thyroid), ears, nose and throat, lymph nodes, cardiovascular, lungs, mammae, abdomen (liver, spleen), genitals, limbs, central and peripheral nervous system, musculoskeletal system, skin & nails, mucosae. The Investigator classified abnormal findings as either clinically significant or not clinically significant.
Time Frame
From Day 1 Up to Day 118
Title
Number of Participants Reporting One or More Treatment Emergent Adverse Events
Description
An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame
From Day 1 Up to Day 118
Secondary Outcome Measure Information:
Title
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MT203
Description
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax
Time Frame
Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
Title
Cmax: Maximum Observed Plasma Concentration for MT203
Description
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time Frame
Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
Title
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MT203
Description
AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]).
Time Frame
Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
Title
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MT203
Description
AUC(0-inf) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau]), where tau is the length of the dosing interval in this study).
Time Frame
Day 29 (Pre-dose and 2 and 6 hours post-dose)
Title
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MT203
Description
Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.
Time Frame
Day 29 (Pre-dose and 2 and 6 hours post-dose)
Title
Terminal Phase Elimination Half-life (T1/2) for MT203
Description
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time Frame
Day 29 (Pre-dose and 2 and 6 hours post-dose)
Title
Ctrough: Maximum Observed Plasma Concentration Pre-Dose
Time Frame
Days 1, 15 and 29 Pre-dose
Title
Change From Baseline in Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Plasma
Description
MT203/GM-CSF complexes were analysed using a procedure that quantified GM-CSF after dissociation from the complex. The determined concentrations corresponded to the amount of total (free and complexed) GM-CSF in the plasma sample. A positive change from Baseline indicated improvement.
Time Frame
Baseline and Days 2, 4, 6, 8 15, 29, 30, 35, 43, 56, 71, 99, End of trial (EOT) Up to Day 118
Title
Change From Baseline in MT203/GM-CSF Complexes in Plasma
Description
MT203/GM-CSF complexes were analysed using a procedure that quantified GM-CSF after dissociation from the complex. The determined concentrations corresponded to the amount of total (free and complexed) GM-CSF in the plasma sample. A positive change from Baseline indicated improvement.
Time Frame
Baseline and Days 2, 4, 6, 8 15, 29, 30, 35, 43, 56, 71, 99, EOT Up to Day 118
Title
Number of Participants With Anti-MT203 Antibodies
Description
Serum samples were tested for the presence of anti-MT203 antibodies by a bridging Electro-chemi-luminescent assay (ECL-assay).
Time Frame
From Day 1 Up to Day 118
Title
Percentage of Participants With American College of Rheumatology (ACR 20) Response
Description
ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant Erythrocyte Sedimentation Rate.
Time Frame
Baseline and Days 13,27,43,56,71,99 and EOT Up to Day 118
Title
Change From Baseline in the Disease Activity Score 44-Erythrocyte Sedimentation Rate (DAS44-ESR)
Description
Ritchie articular index (RAI); a joint count that grades the tenderness of 26 joints on a scale of 0-3); the number of swollen joints from 44 joints (swollen44); ESR in mm/hour after 1 hour and the patient's global disease activity on a Visual Analogue Scale (VAS) of 100 mm (0=no disease activity to right end of the line 100=maximum disease activity) were used to calculate DAS44-ESR using the following formula: DAS44-ESR = 0.54*sqrt(RAI) + 0.065*(swollen44) + 0.33*ln(ESR) + 0.0072*VAS. Lower numbers were better. A negative change from Baseline indicated improvement.
Time Frame
Baseline and Days 13,27,43,56,71,99 and EOT Up to Day 118

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Out-patients with active rheumatoid arthritis (RA), according to the ACR 1987 revised criteria, with low to moderate disease activity (DAS28-ESR ≥ 2.6 and ≤ 5.1) Patients must be on stable doses of methotrexate (MTX) ≥ 7.5 and ≤ 25 mg/week for at least 12 weeks before the first injection, with appropriate folic acid supplementation Age ≥ 18 years at Screening Body weight at least 50 kg at Screening; BMI: ≥ 18.0 and ≤ 30.0 kg/m2 at Screening Negative tuberculosis test at Screening Heterosexually active male and female patients of childbearing potential are obliged to follow whatever contraceptive and / or breastfeeding restrictions may be required for their concomitant medication(s), including methotrexate. In addition, heterosexually active male and female patients of childbearing potential are required to use effective double-method contraception (one hormonal contraceptive or intrauterine device and one other additional contraceptive method) for 1 month before the first administration of the IMP, during the course of the trial, and for 6 month after the last injection of MT203. No special requirements are made for female patients proven to be post-menopausal (at least 2 years after last menstrual period and FSH ≥ 40IU/L), surgically sterilized or hysterectomized. Likewise no special requirements for heterosexually active male who are surgical sterilized. Pregnant or lactating female patients have to be excluded. Exclusion Criteria: Participation in another clinical trial or previous dosing in this trial Use of specified medications within certain timeframes or use of certain comedications History or presence of specified diseases Drug abuse Certain laboratory parameters outside a specified range Donation of blood Relevant decrease in lung function Infections, frequent or chronic infections, herpes zoster Females: positive pregnancy test Presence of history of tuberculosis History of malignancy
Facility Information:
Facility Name
Nycomed Investigational Site
City
Sofia
Country
Bulgaria
Facility Name
Nycomed Investigational Site
City
Leids
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
28274253
Citation
Huizinga TW, Batalov A, Stoilov R, Lloyd E, Wagner T, Saurigny D, Souberbielle B, Esfandiari E. Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis. Arthritis Res Ther. 2017 Mar 9;19(1):53. doi: 10.1186/s13075-017-1267-3.
Results Reference
derived

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A Trial to Evaluate the Safety and Tolerability of Namilumab (MT203) in Patients With Mild to Moderate Rheumatoid Arthritis

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