Cx611-0101, eASCs Intravenous Administration to Refractory Rheumatoid Arthritis Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Cellerix ( TiGenix S.A.U. )
ClinicalTrials.gov Identifier:
NCT01663116
First received: August 5, 2011
Last updated: March 5, 2013
Last verified: February 2013
  Purpose

Phase Ib/IIa clinical trial of a new medicinal product of the somatic cell therapy class (eASCs). This study is designed as a multicenter, single blind, fixed dose escalation, with three treatment groups, controlled with placebo (randomization 3:1) whose target population are patients with rheumatoid arthritis refractory to at least two biologic.


Condition Intervention Phase
Rheumatoid Arthritis Aggravated
Genetic: Stem cells
Genetic: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: "Phase Ib/IIa, Escalating Dose, Single Blind, Clinical Trial to Assess the Safety of the i.v Administration of Allogeneic Adipose-derived Mesenchymal Cells (eASCs) to Refractory Rheumatoid Arthritis (RA) Patients".

Resource links provided by NLM:


Further study details as provided by Cellerix:

Primary Outcome Measures:
  • Number of Adverse Events and Severe Adverse Events [ Time Frame: 6 months follow up after the first administration ] [ Designated as safety issue: Yes ]
    Total number of Adverse Events and Severe Adverse Events, related and non-related with the medication will be recorded as a measure of tolerability and safety.


Secondary Outcome Measures:
  • Proportion of ACR20 patients/ACR50 patients/ACR70 patients (swollen joints*, tender joints**, physician global assessment***, patient global assessment***, patient´s assessment of pain ***, ESR/CRP, HAQ score) [ Time Frame: At selection and screening visit, and once per month during 6 months after the last administration ] [ Designated as safety issue: No ]

Enrollment: 53
Study Start Date: March 2011
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment
  1. first cohort: 1 million stem cells/kg administered at days 1, 8 and 15
  2. second cohort: 2 million stem cells / kg administered at days 1, 8 and 15
  3. third cohort: 4 million stem cells / kg administered at days 1, 8 and 15
Genetic: Stem cells
  1. first cohort: 1 million stem cells/kg administered at days 1, 8 and 15
  2. second cohort: 2 million stem cells / kg administered at days 1, 8 and 15
  3. third cohort: 4 million stem cells / kg administered at days 1, 8 and 15
Placebo Comparator: Placebo
Lactate Ringer´s solution
Genetic: Placebo
  1. first cohort: 20 ml administered at days 1, 8 and 15
  2. second cohort: 40 ml administered at days 1, 8 and 15
  3. third cohort: 80 ml administered at days 1, 8 and 15

Detailed Description:

Traditionally, RA has been treated with non-steroidal anti-inflammatory drugs, glucocorticoids and non-biologics-DMARDs. Only non-biologics-DMARDs and, at a lesser extent, glucocorticoids have shown to be able to prevent or interrupt the inflammatory and destructive disease processes.

Mesenchymal stem cells (MSCs) are nonhematopoietic stromal cells that are able to differentiate into mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs can be easily isolated from bone marrow or adipose tissue and rapidly expanded in culture. MSCs have also been shown to have immuno-suppressive and healing capacities, improve angiogenesis and prevent fibrosis. These properties could be used for novel therapeutic applications in various disorders, including rheumatoid arthritis, osteoarthritis (OA), genetic bone and cartilage disorders and bone metastasis. MSCs can potently modulate immune responses, showing antiproliferative and anti-inflammatory capacities.

This study is a multicenter phase Ib/IIa, escalating dose, single blind clinical trial to assess the safety of the intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) to refractory rheumatoid arthritis (RA) patients.

The primary objective of the study is to determine the safety, feasibility and tolerance, and to identify, if possible, the dose limiting toxicity (DLT) and the dose for future clinical trials on efficacy of the intravenous infusion of allogeneic eASCs for patients suffering rheumatoid arthritis (RA) under treatment with at least one non-biologic-Disease modifying antirheumatoid drug (DMARD) who have previously failed to treatment with at least two biologics. The secondary objective is to obtain information on the clinical and functional effects of the intravenous infusion of allogeneic eASCs in patients with RA and to explore pharmacodynamics parameters.

53 patients (i.e. patients having received at least one dose of study treatment) in three different cohorts are planned to be included in this clinical trial. Expansion will start after acute toxicity assessment of the first three patients of each cohort.

Dose and intervals for the trial consist of the following active groups: a) first cohort: 1 million cells/kg administered at days 1, 8 and 15; b) second cohort: 2 million cells / kg administered at days 1, 8 and 15; c) third cohort: 4 million cells / kg administered at days 1, 8 and 15.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

Patients must meet all the following inclusion criteria to be eligible for study entry:

  1. Must understand and voluntarily sign an informed consent form prior to the conduct of any study related assessment/procedures.
  2. Subjects with RA under treatment with at least one non-biologic-DMARD and failure to treatment with at least two biologics.
  3. Of either gender, aged ≥ 18 years at time of consent.
  4. Able to adhere to the study visit schedule and other protocol requirements.
  5. Have a diagnosis of RA for ≥6 months.
  6. EULAR DAS28-ESR activity criteria >3.2.
  7. Four tender joints to palpation and four swollen joints, based on a 68/66-joint count.
  8. Be receiving treatment on an outpatient basis.
  9. If taking methotrexate, leflunomide, or sulfasalazine, must have been treated for at least 16 weeks and on a stable dose (oral methotrexate ≤ 25 mg/week; parenteral methotrexate ≤ 20 mg/week; leflunomide ≤ 20 mg/day; sulfasalazine ≤ 3 g/day) for at least 4 weeks prior to the start of treatment and throughout the study. (See also section 7.5). The rest of the DMARDs (gold salts, etc) should be maintained at stable doses during at least the 4 weeks prior to the start of treatment and throughout the study (see also section 7.5).
  10. If taking oral corticosteroids, must be on a stable dose of prednisone ≤ 10 mg/day or equivalent for at least 1 month prior to screening. ( See also section 7.5).
  11. If taking NSAIDs, must be on stable dose for at least 2 weeks prior to screening and until they have completed the Week 24 study visit. (See also section 7.5).
  12. Male subjects (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in activity in which conception is possible while on study medication and for at least 28 days after taking the last dose of study medication.
  13. Females of Childbearing Potential* must have a negative urine pregnancy test at Screening and Baseline and must be willing to use one medically approved form of birth control when engaging in activity in which conception is possible while on study medication and for at least 28 days after taking the last dose of study medication.

    • A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral ovariectomy (the surgical removal of both ovaries) or 2) has not been postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months).

Exclusion criteria

A patient CANNOT be recruited into this study if any of the following criteria is met:

  1. Treatment with biologics within the following period prior to the start of treatment:

    1. Infliximab: 8 weeks
    2. Etanercept: 2 weeks
    3. Adalimumab and certolizumab: 4 weeks
    4. Abatacept, tocilizumab and golimumab: 8 weeks
    5. Rituximab: 6 months
    6. Anakinra: 3 days No treatment with biologics is allowed during the first 12 weeks after the start of the study treatment. Thus, the patients should have complied with the periods indicated above, and should not receive any biologics during the period specified.
  2. Presence of a severe bleeding or thrombotic disorder.
  3. History of known pulmonary embolism or known secondary anti-phospholipid syndrome.
  4. Received any of the following treatments within 2 years prior to study entry: anti-cancer therapy (e.g. alkylating agents, anti-metabolites, purine analogues, monoclonal antibodies for malignancy).
  5. Received within 4 weeks prior to the start of treatment: intra-articular, intramuscular or intravenous corticosteroids. (See also section 7.5).
  6. Past or current malignant melanoma.
  7. Past or current malignancy; except for in situ cervical cancer, non-invasive basal cell and squamous cell skin carcinoma, superficial bladder tumors (Ta and Tis) with a complete response duration of >10 years. In the case of lymphoma or breast cancer patients will be allowed to participate in the trial with a complete response duration of >20 years.
  8. Other autoimmune diseases, previous or current inflammatory joint disease other than rheumatoid arthritis, currently active or previous recurrent bacterial, viral, fungal, or other infections including, but not limited to, tuberculosis and atypical mycobacterial disease, clinically significant abnormalities on chest radiograph, hepatitis B and C, and recurrent herpes zoster.
  9. Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, Mycobacterium tuberculosis infection (TB) and active hepatitis B and C.

    For the screening of latent TB, the results of the tests performed in the last year according to the usual practice of the center or local guidelines will be accepted, as long as the investigator rules out a situation of high contact risk in the months after the last screening in accordance with the medical history of the patient.

    If the patient has a recent chest X-ray (performed in the month prior to enrollment in the study) and there is no clinical evidence or history suggestive of recent contact, it will not be necessary to repeat the test.

  10. Subjects with signs of latent TB can be included if they have started treatment according to local guidelines at least one month prior to starting investigational therapy.
  11. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months from screening, congestive heart failure of worse than grade II of the New York criteria.
  12. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease, or evidence of demyelinating disease.
  13. History of significant cerebrovascular disease.
  14. Subjects with congenital or acquired immunodeficiencies.
  15. Known human immunodeficiency virus (HIV) positive.
  16. Screening laboratory values (according to central laboratory):

    • Haemoglobin <5.6 mmol/L (9.0 g/dL).
    • Neutrophils <1.5 x 10(9)/L.
    • Leukocytes <3.0 x 10(9)/L.
    • Platelets <100 x 10(9)/L.
    • Serum IgG <lower limit of normal (LLN).
    • Alanine amino transferase (ALT) > 1.5 times the upper limit of normal (ULN).
    • Total bilirubin >2 mg/dl.
    • Aspartate amino transferase (AST) >1.5 times ULN.
    • Alkaline phosphatase (ALP) >2 times ULN.
    • Creatinine >133 mmol/L (1.5 mg/dL).
  17. Serologic evidence of hepatitis C (HC) infection.
  18. Serologic evidence of hepatitis B (HB) infection based on the results of testing for HBsAg, anti-HBc and anti-HBs antibodies as follows:

    • Subjects positive for HBsAg are excluded.
    • Subjects negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies were eligible to participate.
    • Subjects negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody are eligible to participate.
    • Subjects negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody required clarification of their status by testing for HB DNA which if positive excludes the subject from participation.

      • Patients with documented vaccination against hepatitis B (primary and secondary immunization and booster) are considered negative.
  19. Receipt of any vaccination (live, attenuated or killed) in 8 wks prior to baseline.
  20. Subjects who had received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to screening.
  21. Current participation in any other interventional clinical study.
  22. Subjects known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder).
  23. MRI is unfeasible, (e.g. due to the presence of pacemakers, hip replacements or severe claustrophobia).
  24. Subjects with impossibility of having a radiological exploration.
  25. Known allergies or hypersensitivity to antibiotics, HSA, DMEM, materials of bovine origin, gadolinium (MRI contrast) and Ringer's Lactate Solution.
  26. Pregnancy and breastfeeding.
  27. Any other condition which the PI judges would make patient unsuitable for study participation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01663116

Locations
Spain
Hospital U. Central de Asturias
Oviedo, Asturias, Spain, 33006
Hospital General de Mérida
Mérida, Badajoz, Spain, 06800
Hospital U. de Canarias
La Laguna, Tenerife, Spain, 38320
Hospital de Cruces
Barakaldo, Vizcaya, Spain, 48903
Hospital de Basurto
Bilbao, Vizcaya, Spain, 48013
Complejo Hospitalario U. A Coruña
A Coruña, Spain, 15006
Hospital Clinic i Provincial
Barcelona, Spain, 08036
Hospital Vall d'Hebron
Barcelona, Spain, 08035
Hospital Santa Creu i Sant Pau
Barcelona, Spain, 08041
Hospital Reina Sofía
Córdoba, Spain, 14004
Hospital Clínico San Cecilio
Granada, Spain, 18012
Hospital U. Virgen de las Nieves
Granada, Spain, 18014
Hospital U. de Guadalajara
Guadalajara, Spain, 19002
Hospital Clínico San Carlos
Madrid, Spain, 28040
Hospital U. Gregorio Marañon
Madrid, Spain, 28007
Hospital de La Princesa
Madrid, Spain, 28006
Hospital U. La Paz
Madrid, Spain, 28046
Hospital Carlos Haya
Málaga, Spain, 29010
Hospital U. Marques de Valdecilla
Santander, Spain, 39008
Hospital Virgen Macarena
Sevilla, Spain, 41071
Hospital Ntra. Sª de Valme
Sevilla, Spain, 41014
Hospital La Fe
Valencia, Spain, 46009
Hospital Dr. Peset
Valencia, Spain, 46017
Sponsors and Collaborators
TiGenix S.A.U.
Investigators
Study Chair: José María Alvaro-Gracia, MD, PhD Hospital de la Princesa
  More Information

No publications provided

Responsible Party: Cellerix ( TiGenix S.A.U. )
ClinicalTrials.gov Identifier: NCT01663116     History of Changes
Other Study ID Numbers: Cx611-0101
Study First Received: August 5, 2011
Last Updated: March 5, 2013
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Cellerix:
Rheumatoid arthritis
Expanded adipose derived allogeneic adult stem cells (eASCs)

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on July 29, 2014