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Efficacy of Intradiscal Injection of Autologous BM-MSC in Worker Patients Affected by Chronic LBP Due to Multilevel IDD (ACTIVE)

Primary Purpose

Intervertebral Disc Degeneration, Chronic Low-back Pain

Status

Unknown status

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Autologous BM-MSC

Sham Procedure

About this trial

This is an interventional treatment trial for Intervertebral Disc Degeneration focused on measuring Low back pain, Spine, Intervertebral disc degeneration, Mesenchymal stem cells, Bone marrow

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Workers (it means subject has worked at least 2 months, even if not continuously, in the last 6 months)
Age between 18 and 65 years.
Signed informed consent.
Symptomatic chronic LBP due to moderate/severe IDD [modified Pfirrmann score 3-5 (Pfirrmann et al., 2001), Griffith score 4-8 (Griffith et al., 2007)] at max. 4 levels of the lumbar spine unresponsive to conservative treatment, physical and medical for at least 6 months. Physical treatment includes physiotherapy. Medical treatments includes AINS, paracetamol, opioids and myorelaxant.
Annulus fibrosus intact, demonstrated by MRI.
Pain baseline > 40 mm on VAS (0- 100).
NSAID washout of at least 2 days before screening.
Painkillers washout of at least 24 hours before screening.
For females of childbearing potential, a negative pregnancy test must be documented at Screening.
Men and women should use effective contraception during treatment and for at least 12 months after BM-MSC discontinuation. The complete list of contraceptive methods is described in the patient information sheet and in the paragraph 6.5. As a precautionary measure, breast-feeding should be discontinued during treatment with BM-MSC and should not be restarted after discontinuation of BM-MSC.

Exclusion Criteria:

Non-workers (it means that the person has worked less than 2 months, although not continuously, in the last 6 months)
Congenital or acquired diseases leading to spine deformations that may upset cell application (scoliosis, isthmus lesion, sacralization and hemisacralization, degenerative spondilolisthesis).
Spinal segmental instability assessed by dynamic X-Ray.
Symptomatic facet joints syndrome on MRI (facet joints hyperintensity and hypertrophy evaluated at coronal T2 weighted MRI).
Prior to the screening visit, has received:
- Oral corticosteroid therapy within the previous 3 months, OR
- Intramuscular, intravenous or epidural corticosteroid therapy within the previous 3 months
Presence of a 5th level with symptomatic IDD (modified Pfirrmann score 3-5, Griffith score 4-8) in the lumbar spine.
Spinal canal stenosis (Schizas score > B).
History of spinal infection.
Lumbar disc herniation and sciatica.
Endplate abnormality such as Schmorl's Nodes.
Previous discal puncture or previous spine surgery.
IDD with Modic III changes on MRI images.
Patients not eligible to the intravertebral disc surgery.
Patients who have the risk to undergo a surgery in the next 6 months.
Patients with local infusion device/devices for corticosteroids.
Obesity with body mass index (BMI in Kg/size in m2) greater than 35 (obesity grade II).
Participation in another clinical trial or treatment with another investigational product within 30 days prior to inclusion in the study.
Abnormal blood tests: hepatic (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] >1.5 × upper limit of normal [ULN]), renal, pancreatic or biliary disease, blood coagulation disorders, anemia or platelet count of <100 × 109/L.
Pregnant or lactating women, or premenopausal women not using an acceptable form of birth control, are ineligible for inclusion. Contraception will be maintained during treatment and until the end of relevant systemic exposure. Additional pregnancy testing will be performed at the end of relevant systemic exposure. The patients will be required to use contraception from initial treatment administration until 24 months after the last dose of study drug.
In each case of delayed menstrual period (over 1 month between menstruations), confirmation of absence of pregnancy is strongly recommended. The complete list of contraceptive methods is described in the patient information sheet.
Positive serology for following infection: Syphilis, HIV, Hepatitis B, or C.
Contraindication to MRI assessed by the investigator.
Intolerance or allergy to local anaesthesia.
Any history of Cancer or immunodeficiency disease.
Previous transplantation.

Sites / Locations

Campus Bio-Medico University of RomeRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Autologous BM-MSC injection

Sham Procedure

Arm Description

Two interventions: Bone marrow harvesting from the posterior superior iliac crest region Single injections of a dose of 15 million of autologous BM-MSC each disc affected by IDD (up to 4 discs) via imaging control

Two sham procedures: Simulated bone marrow harvesting without insertion into the posterior iliac crest region Simulated injection under only local anaesthesia without disc injection, without placebo injection.

Outcomes

Primary Outcome Measures

Pain clinical relief

Pain clinical reduction of at least 40 percent on Visual Analogic Scale (VAS) between baseline and month 12. VAS pain scale ranges from 0 to 100, where 0 represents no pain and 100 represents the worst pain imaginable.

Functional disability index improvement

Functional disability reduction of 40 percent on Oswestry Disability Index (ODI, also known as the Oswestry Low Back Pain Disability Questionnaire) at month 12 compared with baseline. ODI scale ranges from 0 to 50 and allows evaluation of disability (0 - 20 percent: minimal disability; 20 - 40 percent: moderate disability; 40 - 60 percent: severe disability; 60 - 80 percent: crippled; 80 - 100 percent: bed-bound or exaggerating their symptoms).

Work ability improvement

Improvement of 10 percent on Work Ability Index (WAI) at month 12 compared to baseline. The WAI is composed of 7 items and is a validated instrument that assesses the individual work ability of an employee. The total WAI score ranges from 7 to 49 and is calculated by summing up the scores of the 7 items.

Secondary Outcome Measures

Measure pain relief of the patient

Assessed by Visual Analogic Scale (VAS). VAS pain scale ranges from 0 to 100: where 0 represents no pain and 100 represents the worst pain imaginable.

Measure functional disability index of the patient

Assessed by ODI (Oswestry Low Back Pain Disability Questionnaire) scale which ranges from 0 to 50 (0 - 20 percent: minimal disability; 20 - 40 percent: moderate disability; 40 - 60 percent: severe disability; 60 - 80 percent: crippled; 80 - 100 percent: bed-bound or exaggerating their symptoms).

Evaluate disability and quality of life evolution of the patient

Assessed by Short Form-36 Health Survey (SF-36) scores which consist of eight 0-100 scaled scores (vitality, physical functioning, bodily pain, general health, perceptions, physical role functioning, emotional role functioning, social role functioning and mental health) where a lower score corresponds to more disability and a higher score corresponds to less disability.

Disability and quality of life evolution

Assessed by the patient and the physician on: pain intensity in the lumbar spine (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme); patient's global assessment of disease activity (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor); physician's global assessment of disease activity (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor).

Assess rescue painkillers medication

Rescue medication use will be recorded throughout the study duration by a diary file.

Structural assessment

Evolution of affected disc(s) by quantitative Magnetic Resonance Imaging (MRI) density measurements with T2 mapping protocol used as an indication of disc fluid and glycosaminoglycans (GAG) content. In addition MRI spectroscopy will provide an assessment of the chemical changes associated with disc degeneration. The "quality" of the patient's lumbar disc will be monitored non invasively using T2 weighted MRI sagittal images and T1spin/echo MRI at the same time points. Lumbar disc grading will be performed in the sagittal T2 weighted images by two experienced physicians independently, who will review each intervertebral disc (from L1-2 to L5-S1) by the modified Pfirrmann criteria.

Evaluation of cost

Comparison of medical and non-medical costs between the two groups of patients. Resource used in each arm will be collected in physical units in the eCRF at the clinical centre as follows: Acute care medical hospitalisations related to IDD Acute care surgical hospitalisations related to IDD Rehabilitation hospitalisations related to IDD Analgesics Work disruption

Incidence of Adverse Events (AE)

Report of Adverse Events (AE). If the study patients do not spontaneously report any AE occurrence since their last visit, they will be interviewed by the investigator filling a study-specific AE checklist for recording of symptoms and complaints.

Assessment of vital signs

During each visit to the study centre, patients will undergo a physical examination with recording of vital signs (temperature, blood pressure, heart rate, height and weight).

Evaluation of blood and urine analysis

During each visit to the study centre, patients will undergo blood sampling for assessment of routine lab tests (Haematology and Biochemistry) and urine analysis (dipstick).

Analysis of chemical biomarkers for tissue degeneration

Assessment of chemical biomarkers for tissue degeneration through MRI spectroscopy. MRI spectroscopy will be used to provide an assessment of the chemical changes associated with disc degeneration (Zuo et al. 2009).

Full Information

NCT ID

NCT04759105

First Posted

January 29, 2021

Last Updated

February 16, 2021

Sponsor

Campus Bio-Medico University

Collaborators

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Center for Outcomes Research and Clinical Epidemiology, Italy

1. Study Identification

Unique Protocol Identification Number

NCT04759105

Brief Title

Efficacy of Intradiscal Injection of Autologous BM-MSC in Worker Patients Affected by Chronic LBP Due to Multilevel IDD

Acronym

ACTIVE

Official Title

Autologous Mesenchymal Stem/Stromal Cells for the Treatment of Workers Affected by Chronic Low Back Pain Due to Multilevel InterVErtebral Disc Degeneration: a Phase IIB Randomized Clinical Trial

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Unknown status

Study Start Date

November 17, 2020 (Actual)

Primary Completion Date

July 31, 2021 (Anticipated)

Study Completion Date

June 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Campus Bio-Medico University

Collaborators

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Center for Outcomes Research and Clinical Epidemiology, Italy

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

ACTIVE is a phase II B efficacy monocenter, prospective, randomized, controlled double blinded trial, in which intra-discal autologous adult BM-MSC therapy will be compared with sham treated controls. This trial will evaluate the efficacy of intradiscal injection of autologous BM-MSCs in workers affected by chronic low back pain (LBP) unresponsive to conventional therapy. The efficacy will be evaluated 12 months after the treatment in terms of pain relief (VAS, Visual Analog Scale), functionality (ODI, Oswestry Disability Index), quality of life (SF36, Short Form - 36) and work ability index (WAI).

Detailed Description

Low back pain (LBP) is the main cause of disability in the world, affecting all occupational sectors with different incidence rates. It is estimated that 60 percent of all workers suffer from LBP during their careers, 10 percent of which become chronic (The Lancet. September 2017). Intervertebral disc degeneration (IDD) is widely recognized as a major contributor to LBP, responsible for at least 40 percent of cases. A key characteristic of IDD is loss of matrix integrity and biomechanical functional failure. Today, no therapy can restore intervertebral disc (IVD) function or provide long-term relief from symptomatic IDD. Current therapies are aimed at pain reduction. When these treatments fail, several types of surgery are performed but they are often related to side effects, disturbance of motion and other biomechanical consequences. New strategies concentrate on treating IDD at an early stage. Encouraging results from phase 1 and 2 clinical trials suggest that cell-based regenerative therapies may provide the world first effective therapy for LBP. LBP patients treated with bone marrow mesenchymal stromal/stem cells (BM-MSC) showed rapid and progressive improvement of functional indexes of 65 percent to 78 percent over 1 year after intradiscal administration without side effect. ACTIVE is an ambitious randomized clinical trial aimed at developing a treatment for IDD based on intradiscal injection of autologous BM-MSC to improve the quality of life of workers and the disability of patients with LBP. ACTIVE main aim is to generate efficacy and safety profiles of single injections of 15 million cells/mL of autologous BM-MSC for each disc affected by IDD (up to 4 discs) versus sham procedure. The regenerative potential of BM-MSC treatment will be assessed by Magnetic Resonance Imaging (MRI) technologies on quarterly basis up to 12 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Intervertebral Disc Degeneration, Chronic Low-back Pain

Keywords

Low back pain, Spine, Intervertebral disc degeneration, Mesenchymal stem cells, Bone marrow

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Patients will be randomized in 2 arms of 26 patients and followed up for 12 months.

Masking

ParticipantCare ProviderOutcomes Assessor

Masking Description

The randomization result will be a treatment code. The treatment code of the patient will be transmitted to local pharmacy. Blinding or masking will be carried out at all stages of packaging and conditioning for shipping following the treatment allocation. Injections used for all groups will be clear and indistinguishable from each other.

Allocation

Randomized

Enrollment

52 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Autologous BM-MSC injection

Arm Type

Experimental

Arm Description

Arm Title

Sham Procedure

Arm Type

Sham Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Autologous BM-MSC

Other Intervention Name(s)

Treated

Intervention Description

intradiscal injection of autologous bone marrow mesenchymal stromal/stem cells

Intervention Type

Other

Intervention Name(s)

Sham Procedure

Other Intervention Name(s)

Sham

Intervention Description

anaesthesia, no disc injection, no placebo injection

Primary Outcome Measure Information:

Title

Pain clinical relief

Description

Time Frame

Baseline to month 12

Title

Functional disability index improvement

Description

Time Frame

Baseline to month 12

Title

Work ability improvement

Description

Time Frame

Baseline to month 12

Secondary Outcome Measure Information:

Title

Measure pain relief of the patient

Description

Assessed by Visual Analogic Scale (VAS). VAS pain scale ranges from 0 to 100: where 0 represents no pain and 100 represents the worst pain imaginable.

Time Frame

Baseline, 1, 3 and 6 months

Title

Measure functional disability index of the patient

Description

Time Frame

Baseline, 1, 3 and 6 months

Title

Evaluate disability and quality of life evolution of the patient

Description

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Disability and quality of life evolution

Description

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Assess rescue painkillers medication

Description

Rescue medication use will be recorded throughout the study duration by a diary file.

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Structural assessment

Description

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Evaluation of cost

Description

Time Frame

12 months

Title

Incidence of Adverse Events (AE)

Description

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Assessment of vital signs

Description

During each visit to the study centre, patients will undergo a physical examination with recording of vital signs (temperature, blood pressure, heart rate, height and weight).

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Evaluation of blood and urine analysis

Description

During each visit to the study centre, patients will undergo blood sampling for assessment of routine lab tests (Haematology and Biochemistry) and urine analysis (dipstick).

Time Frame

Baseline, 1, 3, 6 and 12 months

Title

Analysis of chemical biomarkers for tissue degeneration

Description

Time Frame

Baseline, 3, 6 and 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Workers (it means subject has worked at least 2 months, even if not continuously, in the last 6 months) Age between 18 and 65 years. Signed informed consent. Symptomatic chronic LBP due to moderate/severe IDD [modified Pfirrmann score 3-5 (Pfirrmann et al., 2001), Griffith score 4-8 (Griffith et al., 2007)] at max. 4 levels of the lumbar spine unresponsive to conservative treatment, physical and medical for at least 6 months. Physical treatment includes physiotherapy. Medical treatments includes AINS, paracetamol, opioids and myorelaxant. Annulus fibrosus intact, demonstrated by MRI. Pain baseline > 40 mm on VAS (0- 100). NSAID washout of at least 2 days before screening. Painkillers washout of at least 24 hours before screening. For females of childbearing potential, a negative pregnancy test must be documented at Screening. Men and women should use effective contraception during treatment and for at least 12 months after BM-MSC discontinuation. The complete list of contraceptive methods is described in the patient information sheet and in the paragraph 6.5. As a precautionary measure, breast-feeding should be discontinued during treatment with BM-MSC and should not be restarted after discontinuation of BM-MSC. Exclusion Criteria: Non-workers (it means that the person has worked less than 2 months, although not continuously, in the last 6 months) Congenital or acquired diseases leading to spine deformations that may upset cell application (scoliosis, isthmus lesion, sacralization and hemisacralization, degenerative spondilolisthesis). Spinal segmental instability assessed by dynamic X-Ray. Symptomatic facet joints syndrome on MRI (facet joints hyperintensity and hypertrophy evaluated at coronal T2 weighted MRI). Prior to the screening visit, has received: Oral corticosteroid therapy within the previous 3 months, OR Intramuscular, intravenous or epidural corticosteroid therapy within the previous 3 months Presence of a 5th level with symptomatic IDD (modified Pfirrmann score 3-5, Griffith score 4-8) in the lumbar spine. Spinal canal stenosis (Schizas score > B). History of spinal infection. Lumbar disc herniation and sciatica. Endplate abnormality such as Schmorl's Nodes. Previous discal puncture or previous spine surgery. IDD with Modic III changes on MRI images. Patients not eligible to the intravertebral disc surgery. Patients who have the risk to undergo a surgery in the next 6 months. Patients with local infusion device/devices for corticosteroids. Obesity with body mass index (BMI in Kg/size in m2) greater than 35 (obesity grade II). Participation in another clinical trial or treatment with another investigational product within 30 days prior to inclusion in the study. Abnormal blood tests: hepatic (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] >1.5 × upper limit of normal [ULN]), renal, pancreatic or biliary disease, blood coagulation disorders, anemia or platelet count of <100 × 109/L. Pregnant or lactating women, or premenopausal women not using an acceptable form of birth control, are ineligible for inclusion. Contraception will be maintained during treatment and until the end of relevant systemic exposure. Additional pregnancy testing will be performed at the end of relevant systemic exposure. The patients will be required to use contraception from initial treatment administration until 24 months after the last dose of study drug. In each case of delayed menstrual period (over 1 month between menstruations), confirmation of absence of pregnancy is strongly recommended. The complete list of contraceptive methods is described in the patient information sheet. Positive serology for following infection: Syphilis, HIV, Hepatitis B, or C. Contraindication to MRI assessed by the investigator. Intolerance or allergy to local anaesthesia. Any history of Cancer or immunodeficiency disease. Previous transplantation.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Gianluca Vadalà, MD, PhD

Phone

+39 06 225419187

g.vadala@gmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gianluca Vadalà, MD, PhD

Organizational Affiliation

Campus Bio-Medico University of Rome

Official's Role

Principal Investigator

Facility Information:

Facility Name

Campus Bio-Medico University of Rome

City

Roma

ZIP/Postal Code

00128

Country

Italy

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Gianluca Vadalà, MD, PhD

Phone

+39 06 225419187

g.vadala@gmail.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Efficacy of Intradiscal Injection of Autologous BM-MSC in Worker Patients Affected by Chronic LBP Due to Multilevel IDD

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