Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001047886
Ethics application status
Approved
Date submitted
13/05/2021
Date registered
10/08/2021
Date last updated
4/08/2022
Date data sharing statement initially provided
10/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
To evaluate the safety, tolerability and pharmacokinetics of EQ121 following multiple dose administration in adults with Rheumatoid Arthritis who are on a stable oral methotrexate (MTX) regimen.
Scientific title
A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Administered EQ121 Following Multiple Doses in Adults with Rheumatoid Arthritis on a Stable Dose of Methotrexate
Secondary ID [1] 304052 0
EQ121-010
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid arthritis 321693 0
Condition category
Condition code
Inflammatory and Immune System 319432 319432 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
EQ121 capsule is an oral solid dosage form manufactured at strengths of 1 mg and 12 mg.
Each EQ121 Immediate release (IR) capsule contains EQ121 drug substance; mannitol, pregelatinized starch and microcrystalline cellulose as diluents; croscarmellose sodium as disintegrate; colloidal silicon dioxide as glidant; and magnesium stearate as lubricant.
Approximately 12 adults with RA on a stable oral MTX regimen (15-25 mg/week) will be participating in this study. Eligible participants in New Zealand will receive their weekly dose of oral MTX on Days 1 and 8 and 36 mg of EQ121 orally, twice daily (twelve hours apart) on study days 3 to 8.
Blood samples for the determination of EQ121 concentrations and corresponding PK analysis will be collected on Day 3, Day 7 and Day 8 at pre-dose (morning dose; within 30 minutes prior to dosing); and after the morning dose at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours.
Blood samples for determination of MTX concentration and corresponding PK analysis will be collected on Day 1 at pre-dose (30 minutes prior to dosing), and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose, on Day 2 at 24 and 36 hours post-dose, and Day 3 at 48 hours post-dose; and on Day 8 at pre-dose (30 minutes prior to administering oral MTX and study drug together), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post-dose, on Day 9 at 24 and 36 hours post-dose and on Day 10 at 48 hours post-dose.
Samples may be used to determine concentration of drug metabolites.
Safety oversight will be provided by the Principal Investigator and Medical Monitor. A record will be maintained by the investigational site that will account for all dispensing and return of any used and unused study drug.
Adherence will be assessed using pill count of the capsules returned.
Intervention code [1] 320372 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327299 0
To evaluate the safety, tolerability, and pharmacokinetics of multiple doses of EQ121 in
adults with rheumatoid arthritis (RA) who are on a stable oral methotrexate (MTX)
regimen. Severity should be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Timepoint [1] 327299 0
Outcome is assessed by the incidence of adverse events during the study. Assessment of adverse events will be performed continuously on a daily basis through the duration of the study. Treatment-emergent- Adverse Events will be evaluated from the first administration of study drug until the follow-up/End Of Study visit (day 14) or up to a 30-day follow-up period for Adverse Events deemed related to treatment.
Primary outcome [2] 327338 0
To assess the safety and tolerability of EQ121 in adult, participants with Rheumatoid Arthritis. Outcome is assessed by Vital
signs:
- blood pressure : would be performed on a portable electronic, automatic sphygmomanometer
- pulse rate : will be taken manually
- tympanic temperature : via portable external thermometer
Timepoint [2] 327338 0
Vital sign assessments will be completed at Screening, on Day -1, regularly on each residence day in the clinical research unit and at the final outpatient visit (Day 14).
Primary outcome [3] 327339 0
To assess the safety and tolerability of blood and urine samples via clinical laboratory findings:
- Hematology
- Biochemistry
-Coagulation
- Urinalysis
Timepoint [3] 327339 0
Screening, Day-1, Day 1, day 3, Day 9 and at the final outpatient visit (Day 14).
Secondary outcome [1] 394509 0
To determine the effects of multiple doses of EQ121 on the pharmacokinetics of methotrexate (MTX) through the following parameters: Cmax, Tmax, T1/2, AUClast, AUC48, AUCinf
Timepoint [1] 394509 0
Blood samples for the determination of methotrexate (MTX) concentrations and corresponding PK analysis will be collected at the following time points: on Day 1 (first dose) at pre-dose (within 30 minutes prior to dosing), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose; and on Day 2 at 24 and 36 hours post-dose, and Day 3 at 48 hours post-dose; and on Day 8 at pre-dose (within 30 minutes prior to administering oral MTX and study drug together), 0.5, 1, 1.5, 2, 2.5, 3,4, 6, 8, 12 hours post-dose and on Day 9 at 24 and 36 hours post-dose, and on Day 10 at 48 hours post-dose.
Secondary outcome [2] 394641 0
To determine the effects of stable oral MTX doses on the pharmacokinetics of EQ121 through Cmax Tmax AUCt parameters. Samples to be assessed are blood samples collection on Day 3, Day 7 and Day 8.
Timepoint [2] 394641 0
Blood samples for the determination of EQ121 concentrations and corresponding pharmacokinetic (PK) analysis will be collected at the following time points: on Day 3 at pre-dose, on Day 7 and 8 at pre-dose (within 30 minutes prior to dosing) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post-dose.
Secondary outcome [3] 399200 0
To determine the effects of multiple doses of EQ121 on the pharmacokinetics of and 7-hydroxy methotrexate (MTX) through the following parameters: Cmax, Tmax, T1/2, AUClast, AUC48, AUCinf
Timepoint [3] 399200 0
Blood samples for the determination of 7-hydroxy MTX concentrations and corresponding PK analysis will be collected at the following time points: on Day 1 (first dose) at pre-dose (within 30 minutes prior to dosing), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose; and on Day 15 at pre-dose (within 30 minutes prior to administering oral MTX and study drug together), 0.5, 1, 1.5, 2, 2.5, 3,4, 6, 8, 12, 24, 36 and 48 hours post-dose.

Eligibility
Key inclusion criteria
1. Are capable of giving informed consent and complying with study procedures;
2. Male or female between the ages of 18 and 75 years, inclusive;
3. BMI of 18.0 to 32.0 kg per m2, inclusive, at Screening;
4. Diagnosis of RA based on the 2010 American College of Rheumatology (ACR) per European League Against Rheumatism (EULAR) criteria greater than or equal to 6 months;
5. Patients must have less than or equal to 5 swollen joints (based on 28 joint counts) and less than and equal to 5 tender joints (based on 28 joint counts) at Screening and Baseline Visits;
6. Patients must have been on oral MTX therapy greater than or equal to 3 months and on folic acid for greater than and equal to 4 weeks prior to the first dose of study drug. Subjects must be on a stable dose of oral MTX (15-25 mg per week, given once weekly) with or without sulfasalazine (less than and equal to 3000 mg per day), hydroxychloroquine (less than and equal to 400 mg per day), or chloroquine (less than and equal to 250 mg per day), or leflunomide (10-20 mg/day) for more than or equal to 4 weeks prior to the first dose of study drug and must be able to continue on this stable dose for the duration of the study;
7. If on disease-modifying antirheumatic drugs (DMARDs) other than MTX plus or minus sulfasalazine or hydroxychloroquine or chloroquine or leflunomide, participants must have discontinued these medications for at least 3 months or 5 half-lives, whichever is longer, before the first dose of study drug.
8. If on a current therapy with Janus Kinase (JAK) Inhibitor, participants must have discontinued the JAK inhibitor at least 4 weeks prior to Screening. Participants who have prior exposure to any JAK inhibitor are eligible, unless the JAK inhibitor was discontinued due to safety reasons.
9. Female participants must not be currently breast-feeding, and must meet one of the following criteria:
a. Surgically sterile for at least 3 months prior to Screening by one of the following means:
- Bilateral tubal ligation
- Bilateral salpingectomy (with or without oophorectomy)
- Surgical hysterectomy
- Bilateral oophorectomy (with or without hysterectomy)
b. Postmenopausal, defined as the following:
- Last menstrual period greater than 12 months prior to Screening without an alternative medical cause, AND
- Postmenopausal status confirmed by serum FSH concentration at Screening greater than 40 mIU per mL
c. Female subjects of childbearing potential:
• must not have a positive serum pregnancy test at Screening and must have a negative urine pregnancy test on admission
• must use at least one of the following protocol specified highly effective methods of birth control, AND must agree to use barrier contraception (male condom) during heterosexual intercourse, from the time of Screening until at least 30 days after the last dose of study drug.
- Partner vasectomy (at least 6 months prior to Screening; vasectomized partner should be the sole partner of the female subject)
- Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal, injectable)
- Progestogen-only hormonal contraception (oral, injectable, implantable)
- Implantable device (implantable rod or intrauterine device)
10. Male participants must agree to utilize a highly effective method of contraception (condom) during heterosexual intercoursefrom clinic admission until at least 90 days following the end of study visit and must refrain from donating sperm for this same period.
11. Considered to be in general good health by the Investigator, based on participant’s reported medical history, full physical examination, clinical laboratory tests, 12-lead ECG, chest x-ray, and vital signs;
12. Willing and able to adhere to study restrictions and to be confined at the clinical research center;
13. Participants must be willing to defer receiving prophylactic immunizations (e.g. influenza or coronavirus or pneumococcal vaccines) during the study.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to attend all the study visits or comply with study procedures;
2. Hospital admission or major surgery within 3 months prior to Screening;
3. History of prescription drug abuse, or illicit drug use within 6 months prior to Screening;
4. History of alcohol abuse according to medical history within 6 months prior to Screening; (drinking 14 units of alcohol per week: 1 unit equals to 360 mL of beer, or 37 mL of spirits, or 120 mL of wine) at Screening or upon admission to the clinical site;
5. History of inflammatory joint disease other than RA (e.g., mixed connective tissue disease, seronegative spondyloarthropathy, psoriatic arthritides, Reiter’s syndrome, fibromyalgia, systemic lupus erythematosus, or any arthritides with onset prior to age 17);
6. History of RA disease flares in the preceding 90 days before Screening;
7. Current or expected need for oral corticosteroids (greater than 10 mg prednisone/day or equivalent);
8. Positive blood screen for HIV, hepatitis B core (IgG and IgM) and surface antigen (HBsAg), hepatitis C antibody at Screening;
9. History of any infection requiring treatment with IV anti-infectives within 30 days prior to Admission, or oral anti-infectives within 14 days prior to Admission;
10. History or evidence of active or latent tuberculosis (TB). Participants will be evaluated for latent TB infection. Subjects must demonstrate absence of TB infection or exposure by a negative chest x-ray and a negative QuantiFERON-TB Gold Test at Screening;
11. History of malignancy or evidence of dysplasia, other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma, or localized carcinoma in situ of the cervix;
12. History of myocardial infarction, coronary stenting, greater than Class I angina, or cerebrovascular accident within 6 months prior to the first dose of study drug, or history of cardiac arrest, significant cardiac arrhythmia, pacemaker, or clinically significant cardiovascular disease;
13. History of clinically significant psychiatric, neurologic, respiratory, endocrine, hepatic, or renal disease;
14. Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug: serum aspartate transaminase greater than 1.5 into ULN; serum alanine transaminase greater than 1.5 into ULN; estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease formula less than 40 mL per min per 1.73m2; total WBC count less than 2,500 per µL; absolute neutrophil count less than 1,500 per µL; platelet count less than 100,000 per µL; absolute lymphocyte count less than 1,000 per µL; and hemoglobin less than 10 g per dL.
15. Any condition or finding that in the opinion of the Principal Investigator or designee would put the participant or study conduct at risk if the participant were to participate in the study.
16. Receipt of inducers of CYP2C9 (e.g. rifampin) moderate or strong inhibitors of CYP2C9 (e.g. fluconazole), strong inducers of CYP3A4 (e.g. carbamazepine, phenytoin, rifampin, St. John's Wort) or strong inhibitors of CYP3A4 (e.g. itraconazole, ketoconazole, clarithromycin, telithromycin, nefazodone) from screening through the end of sub study.
17. History of organ transplant, including history of bone marrow transplant

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Sponsor has decided to discontinue the EQ121-010 sub-study 2 (Drug-drug interaction of EQ121 in adults with rheumatoid arthritis (RA) who are on a stable oral methotrexate (MTX) regimen), effective immediately. This results from a business decision to halt development of EQ121 in rheumatoid arthritis. This decision was not because of any newly identified safety signals or safety risks associated with EQ121.
Date of first participant enrolment
Anticipated
31/01/2022
Actual
21/02/2022
Date of last participant enrolment
Anticipated
31/03/2022
Actual
21/02/2022
Date of last data collection
Anticipated
30/04/2022
Actual
19/04/2022
Sample size
Target
12
Accrual to date
Final
1
Recruitment outside Australia
Country [1] 23621 0
New Zealand
State/province [1] 23621 0
Christ Church

Funding & Sponsors
Funding source category [1] 308435 0
Commercial sector/Industry
Name [1] 308435 0
EQRx, Inc
Country [1] 308435 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
EQRx, Inc
Address
50 Hampshire Street, Cambridge, MA 02139, USA
Country
United States of America
Secondary sponsor category [1] 309267 0
None
Name [1] 309267 0
Address [1] 309267 0
Country [1] 309267 0
Other collaborator category [1] 281760 0
Commercial sector/Industry
Name [1] 281760 0
Novotech (Australia) Pty Limited
Address [1] 281760 0
Novotech (Australia) Pty Limited, Level 3, 235 Pyrmont Street Sydney, NSW, Australia - 2009
Country [1] 281760 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308393 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 308393 0
Health and disability Ethics Committees, Ministry of Health, 133 Molesworth Street, PO Box 5013, Wellington, 6001
Ethics committee country [1] 308393 0
New Zealand
Date submitted for ethics approval [1] 308393 0
29/04/2021
Approval date [1] 308393 0
04/06/2021
Ethics approval number [1] 308393 0

Summary
Brief summary
This is a Phase 1, open-label study to evaluate the safety, tolerability, and pharmacokinetics of EQ121 following multiple dose administration in adults with RA who are on a stable oral MTX regimen.
Trial website
Trial related presentations / publications
Public notes
Exclusion Criteria:
Evidence of SARS-CoV-2 infection or Oral temperature greater than 38 °C at Admission.

Contacts
Principal investigator
Name 110562 0
Dr Chris Wynne
Address 110562 0
Christchurch Clinical Studies Trust Ltd, Level 4/264 Antigua Street, Christchurch Central City, Christchurch, New Zealand, 8011
Country 110562 0
New Zealand
Phone 110562 0
+6433729477
Fax 110562 0
Email 110562 0
[email protected]
Contact person for public queries
Name 110563 0
Ms Jessie Kane
Address 110563 0
Auckland Clinical Studies, ACS House, Ground Floor, 3 Ferncroft Street, Grafton, Auckland 1010
Country 110563 0
New Zealand
Phone 110563 0
+64 800 788 3437 117
Fax 110563 0
Email 110563 0
[email protected]
Contact person for scientific queries
Name 110564 0
Dr Ramandeep Sharma
Address 110564 0
Novotech (Australia) Pty Limited,
PO Box: 244 Pyrmont NSW 2009
Level 2, 15-31 Pelham Street Carlton VIC 3053, Australia.
Country 110564 0
Australia
Phone 110564 0
+61 3 9341 1998
Fax 110564 0
Email 110564 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.