Phase IIa Proof-of-Concept Study to Investigate the Efficacy, Safety, and Tolerability of FBL-MTX in Patients with Rheumatoid Arthritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Solfarcos Solucoes Farmaceuticas E Cosmeticas Lda.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

24 Jul 2024 → ongoing

Decision date (initial)

2024-05-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

SOLFARCOS – Soluções Farmacêuticas e Cosméticas, Lda.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To evaluate the efficacy of FBL-MTX administered by subcutaneous (SC) route in RA patients.

Secondary objectives 3

1. To evaluate the safety and tolerability of FBL-MTX by SC route in patients with RA.
2. To evaluate FBL-MTX pharmacokinetics in RA patients following a 2.5 mg dose by SC route.
3. To evaluate the efficacy of FBL-MTX after 12 additional weeks of administration, in patients where significant therapeutic gain is achieved ((i.e. attained the target efficacy and present an acceptable tolerability safety) after the first 14 weeks of administration, if the research physician considers that it could be beneficial to the patient and the patient accepts to continue the study medication.

Conditions and MedDRA coding

Rheumatoid arthritis (RA)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

National Authority Of Medicines And Health Products

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 24

1. Free written informed consent prior to any procedure required by the study.
2. Willingness to accept and comply with all study procedures and restrictions.
3. DMARD-naïve RA patient or RA patient with an inadequate response or intolerance to oral MTX.
4. Male or female participant ≥ 18 years, at the time of signing the informed consent.
5. Body mass index (BMI) of 18.5 to 35.0 kg/m2, inclusive.
6. Diagnosis of RA according to the 2010 classification criteria of the ACR/EULAR, with a Total Score ≥ 6/10.
7. At least moderately active disease, as defined by DAS28-CRP >3.2 at Screening and Baseline, including: a) Tender joint count (TJC) ≥ 4; b) Swollen joint count (SJC) ≥ 4; c) C-Reactive protein (CRP) ≥ upper limit of normal; d) Documented history of positive RA factor and/or cyclic citrullinated peptide antibody test.
8. Chest X-ray performed in the previous 3 months not suggestive of tuberculosis.
9. If under NSAIDs therapy, must be able to be in a stable dosing regimen from at least 2 weeks before baseline up to EoS.
10. If under oral corticosteroid therapy (≤ 10mg per day of prednisone or equivalent), must be able to be on a stable regimen from at least 4 weeks before baseline up to up to EoS.
11. Eligible to start treatment with an immunomodulator.
12. No clinically relevant diseases other than RA captured in medical history.
13. No clinically relevant findings other than RA-related captured on physical examination.
14. No clinically relevant abnormalities on vital signs.
15. No clinically relevant abnormalities on 12-lead ECG.
16. No clinically relevant abnormalities on clinical laboratory tests.
17. No evidence of clinically significant active infection.
18. Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab).
19. Negative results from either the hepatitis B or C serology based on hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, total hepatitis B core antibody (IgM will be measured if total anti-hepatitis B core antibody is positive), and hepatitis C virus (HCV) antibody (anti-HCVAb) markers, except for vaccinated subjects or subjects with past resolved hepatitis.
20. A female participant is eligible if she meets one of the following criteria: a) is of non-childbearing potential; or b) is of childbearing potential and agrees to use an highly effective contraceptive method from at least 4 weeks prior to admission to study period until at least 6 months after the last investigational product administration.
21. A male participant who is sexually active with a female partner of childbearing potential (pregnant or non-pregnant) must use contraception (condom) from admission until at least 90 days following the last investigational product administration.
22. A male participant must ensure that his non-pregnant female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception
23. A male participant must be willing not to donate sperm from admission until 90 days following the last investigational product administration.
24. At least moderately active disease, as defined by DAS28-CRP >3.2, including: a) Tender joint count (TJC) ≥ 4 b) Swollen joint count (SJC) ≥ 4 c) C-Reactive protein (CRP) ≥ upper limit of normal; d) Documented history of positive RA factor and/or cyclic citrullinated peptide antibody test.

Exclusion criteria 26

1. Known hypersensitivity / allergy reaction to MTX or any of the excipients.
2. Positive Interferon-Gamma Release Assay (IGRA), in the previous 3 months, unless the patient received previous treatment for tuberculosis (with documented evidence) or presents conditions and is willing to initiate latent tuberculosis treatment (to guarantee, at least, 4 weeks of treatment before baseline).
3. Known severe hypersensitivity reaction to any other drug.
4. Any medical condition (e.g., gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g., cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or participant safety.
5. History of drug or alcohol abuse.
6. History of short QT syndrome, long QT syndrome, or clinically significant cardiac arrhythmia.
7. Family history of sudden death before 40 years old, short, or long QT syndrome.
8. Resting heart rate < 50 bpm in ECG.
9. Baseline QTcF interval > 450 msec if man or > 470 msec if woman, or < 350 msec.
10. History of liver impairment (Child-Pugh B or C).
11. Systolic Blood Pressure (SBP) < 90 mmHg and/or Diastolic Blood Pressure (DBP) <45 mmHg.
12. SBP > 160 mmHg and/or DBP > 95 mmHg.
13. Estimated renal creatinine clearance (CLCr) below the lower limit of normal range (60 mL/min), based on CLCr calculation by the Cockcroft-Gault formula and normalized to an average body surface area of 1.73 m2
14. Positive result in drugs-of-abuse and ethanol tests.
15. Use of a depot injection or an implant of any drug (except for contraceptives) within the previous 6 months.
16. Previous treatment with any of following: a) oral or injectable gold within 4 weeks prior to Day 1; b) sulfasalazine within 4 weeks prior to Day 1; c) azathioprine within 4 weeks prior to Day 1; d) D penicillamine within 4 weeks prior to Day 1; e) cyclosporine within 8 weeks prior to Day 1; f) MTX within 4 weeks prior to Day 1; g) leflunomide within 8 weeks prior to Day 1 or a minimum 4 weeks prior to Day 1, if after 11 days of standard cholestyramine therapy; h) any cytotoxic agent, including chlorambucil, cyclophosphamide, nitrogen mustard, and other alkylating agents; i) any JAK inhibitor or other small molecule immunomodulator; j) potent Pg-p inducer (e.g. rifampin, phenytoin, carbamazepine, and St. John's wort) within 3 weeks prior to Day 1; k) metamizole and other hematotoxic drugs, anticonvulsants, and 5-fluorouracil within 4 weeks prior to admission; l) substances that may have adverse effects on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine) within 4 weeks prior to Day 1.
17. Participation in any clinical trial within the previous 4 weeks or 5 half-lives of the investigational medicinal product (IMP).
18. Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
19. Veins unsuitable for IV puncture on either arm (for patients in the pharmacokinetics group).
20. If woman of childbearing potential (WOCBP), positive pregnancy test.
21. If woman, she is breast-feeding.
22. Any other condition that the Investigator considers to render the participant unsuitable for the study.
23. Any recent disease or condition or treatment that, according to the Investigator, would put the participant at undue risk due to study participation.
24. Positive result in drugs-of-abuse and ethanol tests.
25. If WOCBP, positive urinary pregnancy test.
26. Any other condition that the Investigator considers to render the participant unsuitable for the study period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 11

1. Change from baseline in Disease Activity Score (DAS) for 28-joint count using C-reactive protein (DAS28-CRP) at Week 14.
2. Change from baseline in DAS28-CRP at Weeks 4, 8, and 12.
3. Number of subjects who achieve remission (DAS28-CRP <2.6) at Weeks 4, 8, 12, and 14.
4. Number of subjects who achieve low disease activity (DAS28-CRP <3.2) at Weeks 4, 8, 12, and 14.
5. Number of subjects who achieve American College of Rheumatology (ACR) 20% (ACR20) response at Weeks 4, 8, 12, and 14.
6. Number of subjects who achieve ACR50 response at Weeks 4, 8, 12, and 14.
7. Number of subjects who achieve ACR70 response at Weeks 4, 8, 12, and 14.
8. Change from baseline in Clinical Disease Activity Index (CDAI) at Weeks 4, 8, 12, and 14.
9. Change from baseline in Simplified Disease Activity Index (SDAI) at Weeks 4, 8, 12, and 14.
10. Change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) score at Weeks 4, 8, 12, and 14.
11. Change from baseline in Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) at Week 14.

Secondary endpoints 6

1. Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Clinically relevant abnormalities in vital signs, 12-lead ECG, and laboratory parameters will be reported as AEs.
2. Change from baseline at each scheduled time point of measurement in laboratory parameters (hematology and biochemistry).
3. Pharmacokinetic parameters: Cmax; Time of occurrence of Cmax; Time of observation prior to the first measurable (non-zero) drug concentration; Area under the concentration versus time curve (AUC) from time of dosing to the time of last measurable concentration; AUC extrapolated to infinity; Apparent terminal elimination rate constant; Apparent terminal elimination half-life; Apparent volume of distribution; and Apparent total body clearance.
4. Change from baseline in DAS28-CRP every 4 weeks.
5. Change in SF-36 every 4 weeks.
6. Incidence of TEAEs and SAEs. Clinically relevant abnormalities in vital signs, 12-lead ECG and laboratory parameters will be reported as AEs.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Solfarcos Solucoes Farmaceuticas E Cosmeticas Lda.

Sponsor organisation

Solfarcos Solucoes Farmaceuticas E Cosmeticas Lda.

Address

Avenida Imaculada Conceicao N. 587 E 589

City

Braga

Postcode

4700-034

Country

Portugal

Scientific contact point

Organisation

Solfarcos Solucoes Farmaceuticas E Cosmeticas Lda.

Contact name

Solfarcos – Soluções Farmacêuticas e Cosméticas, Lda.

Public contact point

Organisation

Solfarcos Solucoes Farmaceuticas E Cosmeticas Lda.

Contact name

Solfarcos – Soluções Farmacêuticas e Cosméticas, Lda.

Third parties 3

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications