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

perjantai 24. heinäkuuta 2015 päivittänyt: Takeda

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

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.

Tutkimuksen yleiskatsaus

Tila

Valmis

Ehdot

Interventio / Hoito

Yksityiskohtainen kuvaus

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.

Opintotyyppi

Interventio

Ilmoittautuminen (Todellinen)

24

Vaihe

  • Vaihe 1

Yhteystiedot ja paikat

Tässä osiossa on tutkimuksen suorittajien yhteystiedot ja tiedot siitä, missä tämä tutkimus suoritetaan.

Opiskelupaikat

  • Alankomaat
      • Leids, Alankomaat
        • Nycomed Investigational Site
  • Bulgaria
      • Sofia, Bulgaria
        • Nycomed Investigational Site

Osallistumiskriteerit

Tutkijat etsivät ihmisiä, jotka sopivat tiettyyn kuvaukseen, jota kutsutaan kelpoisuuskriteereiksi. Joitakin esimerkkejä näistä kriteereistä ovat henkilön yleinen terveydentila tai aiemmat hoidot.

Kelpoisuusvaatimukset

Opintokelpoiset iät

18 vuotta ja vanhemmat (Aikuinen, Vanhempi Aikuinen)

Hyväksyy terveitä vapaaehtoisia

Ei

Sukupuolet, jotka voivat opiskella

Kaikki

Kuvaus

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

Opintosuunnitelma

Tässä osiossa on tietoja tutkimussuunnitelmasta, mukaan lukien kuinka tutkimus on suunniteltu ja mitä tutkimuksella mitataan.

Miten tutkimus on suunniteltu?

Suunnittelun yksityiskohdat

  • Ensisijainen käyttötarkoitus: Hoito
  • Jako: Satunnaistettu
  • Inventiomalli: Yksittäinen ryhmätehtävä
  • Naamiointi: Nelinkertaistaa

Aseet ja interventiot

Osallistujaryhmä / Arm
Interventio / Hoito
Kokeellinen: Namilumab 150 mg
Namilumab (MT203) 150 mg (low dose), subcutaneous (SC) injection, on Days 1, 15 and 29.
Lääke: namilumab (MT203)
administered three times, subcutaneous in the abdomen
Kokeellinen: Namilumab 300 mg
Namilumab (MT203) 300 mg (high dose), SC injection, on Days 1, 15 and 29.
Lääke: namilumab (MT203)
administered three times, subcutaneous in the abdomen
Placebo Comparator: Placebo
Namilumab-matching placebo, SC injection, on Days 1, 15 and 29.
Lääke: Placebo
administered three times, subcutaneous in the abdomen

Mitä tutkimuksessa mitataan?

Ensisijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Number of Participants With Clinically Significant Clinical Laboratory Results
Aikaikkuna: From Day 1 Up to Day 118
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.
From Day 1 Up to Day 118
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
Aikaikkuna: From Day 1 Up to Day 118
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).
From Day 1 Up to Day 118
Number of Participants With Clinically Significant Vital Signs
Aikaikkuna: From Day 1 Up to Day 118
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).
From Day 1 Up to Day 118
Number of Participants With Clinically Significant Pulmonary Function Tests
Aikaikkuna: From Day 1 Up to Day 118
Pulmonary function was determined by forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak flow.
From Day 1 Up to Day 118
Number of Participants With Clinically Significant Physical Examination Findings
Aikaikkuna: From Day 1 Up to Day 118
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.
From Day 1 Up to Day 118
Number of Participants Reporting One or More Treatment Emergent Adverse Events
Aikaikkuna: From Day 1 Up to Day 118
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.
From Day 1 Up to Day 118

Toissijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MT203
Aikaikkuna: Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax
Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
Cmax: Maximum Observed Plasma Concentration for MT203
Aikaikkuna: Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MT203
Aikaikkuna: Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
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]).
Day 1 and 29 (Pre-dose and 2 and 6 hours post-dose)
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MT203
Aikaikkuna: Day 29 (Pre-dose and 2 and 6 hours post-dose)
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).
Day 29 (Pre-dose and 2 and 6 hours post-dose)
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MT203
Aikaikkuna: Day 29 (Pre-dose and 2 and 6 hours post-dose)
Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.
Day 29 (Pre-dose and 2 and 6 hours post-dose)
Terminal Phase Elimination Half-life (T1/2) for MT203
Aikaikkuna: Day 29 (Pre-dose and 2 and 6 hours post-dose)
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Day 29 (Pre-dose and 2 and 6 hours post-dose)
Ctrough: Maximum Observed Plasma Concentration Pre-Dose
Aikaikkuna: Days 1, 15 and 29 Pre-dose
Days 1, 15 and 29 Pre-dose
Change From Baseline in Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Plasma
Aikaikkuna: Baseline and Days 2, 4, 6, 8 15, 29, 30, 35, 43, 56, 71, 99, End of trial (EOT) Up to Day 118
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.
Baseline and Days 2, 4, 6, 8 15, 29, 30, 35, 43, 56, 71, 99, End of trial (EOT) Up to Day 118
Change From Baseline in MT203/GM-CSF Complexes in Plasma
Aikaikkuna: Baseline and Days 2, 4, 6, 8 15, 29, 30, 35, 43, 56, 71, 99, EOT Up to Day 118
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.
Baseline and Days 2, 4, 6, 8 15, 29, 30, 35, 43, 56, 71, 99, EOT Up to Day 118
Number of Participants With Anti-MT203 Antibodies
Aikaikkuna: From Day 1 Up to Day 118
Serum samples were tested for the presence of anti-MT203 antibodies by a bridging Electro-chemi-luminescent assay (ECL-assay).
From Day 1 Up to Day 118
Percentage of Participants With American College of Rheumatology (ACR 20) Response
Aikaikkuna: Baseline and Days 13,27,43,56,71,99 and EOT Up to Day 118
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.
Baseline and Days 13,27,43,56,71,99 and EOT Up to Day 118
Change From Baseline in the Disease Activity Score 44-Erythrocyte Sedimentation Rate (DAS44-ESR)
Aikaikkuna: Baseline and Days 13,27,43,56,71,99 and EOT Up to Day 118
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.
Baseline and Days 13,27,43,56,71,99 and EOT Up to Day 118

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Sponsori

Takeda

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Opintojen ennätyspäivät

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Tiistai 1. maaliskuuta 2011

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Opintojen valmistuminen (Todellinen)

Torstai 1. elokuuta 2013

Opintoihin ilmoittautumispäivät

Ensimmäinen lähetetty

Perjantai 18. helmikuuta 2011

Ensimmäinen toimitettu, joka täytti QC-kriteerit

Keskiviikko 16. maaliskuuta 2011

Ensimmäinen Lähetetty (Arvio)

Torstai 17. maaliskuuta 2011

Tutkimustietojen päivitykset

Viimeisin päivitys julkaistu (Arvio)

Torstai 20. elokuuta 2015

Viimeisin lähetetty päivitys, joka täytti QC-kriteerit

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Keskiviikko 1. heinäkuuta 2015

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Muut tutkimustunnusnumerot

  • M1-1188-002-EM
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  • U1111-1137-3923 (Rekisterin tunniste: WHO)
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