| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10031161 |
| E.1.2 | Term | Osteoarthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
TDU13828: To assess the safety and tolerability of ascending single intra-articular doses of GZ389988A in patients with painful osteoarthritis (OA) of the knee.
ACT13830: To assess the efficacy of a single intra-articular dose of GZ389988A compared to placebo for relief of knee pain in patients with osteoarthritis (OA) of the knee |
|
| E.2.2 | Secondary objectives of the trial |
TDU13828: To assess the pharmacokinetic parameters of ascending single intra-articular doses of GZ389988A in patients with painful OA of the knee.
To obtain preliminary pharmacodynamics evaluation of ascending single intra-articular doses of GZ389988A in patients with painful OA of the knee.
ACT13830: To assess the safety and tolerability of a single intra-articular dose of GZ389988A in patients with painful OA of the knee.
To assess the pharmacokinetic parameters of a single intra-articular dose of GZ389988A in patients with painful OA of the knee.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
TDU13828:
Men or women 40 to 60 years of age.
Diagnosis of primary knee osteoarthritis, based upon the following:
- Fulfilling the American College of Rheumatology Clinical and
Radiographic criteria for OA (at least knee pain and osteophytes), with - X-ray or magnetic resonance imagng (MRI) evidence within the last 6 months for Kellgren and Lawrence classification II to IV.
- Western Ontario and Mcmaster Universities Arthrities Index (WOMAC)
A1 Pain subscore (walking pain) between 50 and 90 using the 100-mm visual analogue scale (VAS), corresponding to moderate to severe pain in the index knee, at both screening and baseline assessments at least 48 hours apart.
Symptomatic for more than 6 months (if both symptomatic knees, at least for the most painful knee that will receive the study drug).
Having given written informed consent prior to any procedure related to the study.
Ambulatory with an active lifestyle and in good general health. (Assistive devices were allowed if used throughout a period of 3 months or more prior to screening, on the condition that they continued to be used throughout the study.)
ACT13830:
Men or women 40 to 80 years of age.
Diagnosis of primary knee OA, based upon the following:
- Fulfilling the American College of Rheumatology Clinical and
Radiographic criteria for OA (at least knee pain and osteophytes), with
- X-ray evidence within the last 6 months for Kellgren and Lawrence
classification II to IV.
- Western Ontario and McMaster Universities Arthritis Index (WOMAC)
A1 Pain subscore (walking pain) over the last 48 hours ≥ 40 and ≤ 90 on
VAS 0-100 in the target knee at screening with or without medication,
and ≤ 30 on VAS 0-100 in the contralateral knee at screening with or
without medication.
- WOMAC A1 pain subscore (walking pain) between 50 and 90 using the
VAS 0-100, corresponding to moderate to severe pain in the target knee
at baseline (from eDiary, average of at least 3 days in the time window
between Day-5 and Day-1).
Symptomatic for more than 6 months (if both symptomatic knees, at
least for the most painful knee that will receive the study drug).
Having given written informed consent prior to any procedure related to
the study.
Ambulatory with an active lifestyle and in good general health. (Assistive
devices were allowed if used throughout a period of 3 months or more
prior to screening, on the condition that they continue to be used
throughout the study).
A male who is sexually active must use a condom as part of a method of
highly effective contraception (eg, condom + spermicide, and an
additional contraceptive method used by the partner) during sexual
intercourse with a women of childbearing potential for the duration of
the study period up to the end-of-study visit and should not father a
child in this period. Male patients also have to agree not to donate sperm
for the duration of the study until the end-of-study visit. |
|
| E.4 | Principal exclusion criteria |
TDU13828:
Women of child bearing potential.
Any uncontrolled, chronic condition or laboratory finding which, in the opinion of the Investigator, could potentially put the patient at increased risk.
Patients with clinically significant or uncontrolled hepatic,
gastrointestinal, cardiovascular, respiratory, neurological (including diabetic neuropathy), psychiatric, hematological, renal, or dermatological disease, or any other medical condition that might interfere with the evaluation of the investigational medicinal product (IMP) according to Investigator's medical judgment.
Chondrocalcinosis.
Fibromyalgia.
Major depression.
History or presence of drug or alcohol abuse (alcohol consumption >40 grams per day).
Any patient who, in the judgment of the Investigator, is likely to be noncompliant during the study, or unable to cooperate because of a language problem or poor mental development.
Abnormal coagulation parameters: outside the range international normalized ratio (INR) 0.85-1.15, activated partial thromboplastin time
>33 seconds, platelets <140x10^9 /L.
Moderate to severe renal impairment.
Underlying hepatobiliary disease and/or alanine aminotransferase (ALT)
>2 x upper limit of normal (ULN).
High sensitivity C-reactive protein (hsCRP) > 2 x ULN.
Hemoglobin <10 g/dL, white blood cell count (WBC) <3 x 10^9/L.
Positive result on any of the following tests: hepatitis B surface (HBs Ag) antigen, anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 Ab).
Secondary OA.
Ipsilateral hip OA.
Symptomatic contralateral knee OA with WOMAC A1 pain subscore (walking pain) >30 on 100-mm VAS.
History of osteonecrosis and/or rapidly progressive OA.
Intra-articular injection within 3 months prior to inclusion.
Unable to be maintained for at least 2 weeks prior to entry into study on paracetamol (No non-steroidal non-inflammatory drugs [NSAID] use during the 12 weeks of the study; after the end-of-study visit [Day 84 ±
7] patients may be given a NSAID if necessary to provide better control of OA symptoms).
Any Investigational Medicinal Product within 3 months prior to the study.
ACT13830:
Women of childbearing potential.
Pregnant or breastfeeding women.
Any uncontrolled, chronic condition or laboratory finding which, in the
opinion of the Investigator, could potentially put the patient at increased
risk.
Patients with clinically significant or uncontrolled hepatic,
gastrointestinal, cardiovascular, respiratory, neurological (including
diabetic neuropathy), psychiatric, hematological, renal, or
dermatological disease, or any other medical condition, such as
symptomatic peripheral vascular disease of the study leg (prior or
current), clinically significant venous or lymphatic stasis present in the
study leg, that might interfere with the evaluation of investigational
medicinal product (IMP) according to Investigator's medical judgment.
Chondrocalcinosis.
Fibromyalgia.
Moderately severe or severe depression as indicated by Patient Health
Questionnaire-9 (PHQ-9) total score at screening visit.
Severe anxiety as indicated by Generalized Anxiety Disorder (GAD-7)
score at screening visit.
History or presence of drug or alcohol abuse (alcohol consumption >40
grams per day)
Any patient who, in the judgment of the Investigator, is likely to be
noncompliant during the study, or unable to cooperate because of a
language problem or poor mental development, or unable to use an
electronic diary daily.
Abnormal coagulation parameters: outside the range international normalized ratio (INR) 0.85-1.15, activated partial thromboplastin time
>33 seconds, platelets <140 x 10^9/L.
Moderate to severe renal impairment.
Underlying hepatobiliary disease and/or alanine aminotransferase (ALT)
>2 x upper limit of normal (ULN).
High sensitivity C-reactive protein (hsCRP) >2 x ULN.
Hemoglobin <10 g/dL, white blood cell count (WBC) <3 x 10^9/L.
Positive result on any of the following tests: hepatitis B surface antigen
(HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, anti-human
immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2
Ab).
Secondary OA.
Ipsilateral hip OA.
History of osteonecrosis and/or rapidly progressive OA (RPOA).
Intraarticular injection within 3 months prior to inclusion.
Unable to be maintained for at least 2 weeks prior to entry into study on
paracetamol (no non-steroidal anti-inflammatory drug [NSAID] use
during the 12 weeks of the study; after the end of study visit [Day 84 ±
7] patients may be given an NSAID if necessary to provide better control
of OA symptoms).
Any IMP within 3 months prior to the study.
Any knee MRI contraindication.
Patients at risk of developing a RPOA with pre-existing findings on MRI
of the target knee at baseline.
Patients with painDETECT questionnaire (PD-Q) score > 18. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
TDU13828
1.Proportion of patients with adverse events;
2.Proportion of patients with clinically significant changes in physical examination, vital signs and 12-lead electrocardiogram;
3.Proportion of patients with clinically significant changes in laboratory tests including hematology, biochemistry and urinalysis.
ACT13830:
Change from baseline in weekly mean score of WOMAC A1 pain subscore (walking pain) collected daily in the target knee, as measured by the VAS 0-100 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
TDU13828
1.Up to Day 84 after single intra-articular dose of GZ389988A, followed by a safety follow-up period over 12 additional weeks (by phone calls)
2. and 3.: Up to Day 84 after single intra-articular dose of GZ389988A
ACT13830:
Averaged over 4 weeks (up to Day 28) |
|
| E.5.2 | Secondary end point(s) |
TDU13828:
Assessment of pharmacokinetic parameters:
1.Maximum plasma concentration (Cmax) of GZ389988A single dose
intra-articular (IA)
2.Area under the curve from time zero to last quantifiable concentration
(AUClast) of single dose GZ389988A IA
3.Area under curve (AUC) of single dose GZ389988A IA
4.Plasma elimination half-life (t1/2z) of single dose GZ389988A IA
5.Time to peak plasma concentration (tmax) of single dose GZ389988A
IA
dose GZ389988A IA
7.Apparent volume of distribution (Vz/F) of single dose GZ389988A IA
8.Apparent total body clearance(CL/F) of single dose GZ389998A IA
9.Synovial fluid concentrations (if possible) of single dose GZ389988A
IA
10.Change from baseline in WOMAC index (total score)
11.Change from baseline in WOMAC pain (including WOMAC A1 pain
subscores)
12.Change from baseline in WOMAC stiffness and physical function
subscores
ACT13830:
1.Change from baseline in weekly mean score of WOMAC A1 pain
subscore (walking pain) collected daily in the target knee, as measured
by the VAS 0-100
2.Change from baseline in weekly mean score of WOMAC A1 pain
subscore collected daily in the target knee
3.Change from baseline in weekly mean score of WOMAC A1 pain
subscore collected daily in the target knee
4.Change from baseline in weekly mean score of overall knee pain
collected daily in the target knee
5.Change from baseline in patient global assessment (PGA) of disease
status
6. Change from baseline in WOMAC index (total score for pain, stiffness,
and physical function subscales), pain, stiffness and physical function
subscores
7. Patient Global Impression of Change (PGIC)
8. Patient's global assessment of response to therapy (PGART)
9. Rate of response to therapy according to OMERACT-OARSI
10. WOMAC A1 responder rate based on percentage of patients with
reduction in pain intensity of at least 30% and 50% at endpoint
compared to baseline
11. Time to first WOMAC A1 response for both ≥30% and 50%
reductions in pain intensity
12. Amount of rescue medication intake |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
TDU13828:
1.,2.,3.,4.,5.,6.,7.,8. : 24 timepoints up to Day 84
9. 3 timepoints up to Day 84
10., 11.,12. : over 1, 2, 3, 4, 6, 8, 10, and 12 weeks following the single
intra-articular injection
ACT13830:
1. Averaged over 12 weeks (up to Day 84)
2. Averaged over 1, 2, 3, 6, 8, and 10 weeks
3. At 1,2,3,4,6,8,10 and 12 weeks.
4. and 5. : At and averaged over 1, 2, 3, 4, 6, 8, 10, and 12 weeks
6. Averaged over 1, 2, 3, 4, 6, 8, 10, and 12 weeks
7. and 8. : over the last four weeks at Day 28 (1 to 4 weeks), Day 56 (5
to 8 weeks), and Day 84 (9 to 12 weeks)
9. By Day 28, Day 56, and Day 84
10. Over 4 weeks (up to Day 28) and 12 weeks (up to Day 84) and at 1,
2, 3, 4, 6, 8, 10, and 12 week
11. At 1, 2, 3, 4, 6, 8, 10, 12 weeks
12. Up to day 84 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Ascending dose (TDU13828) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of the trial after the 12-week safety follow-up by phone calls following the end-of-study visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 17 |
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