Cerebral Palsy
Conditions
Keywords
CP, Cerebral Palsy, Stem Cell, Cord Blood, MSCs
Brief summary
The main purpose of this study is to estimate change in motor function 12 months after treatment with a single dose of allogeneic umbilical cord blood (AlloCB) or repeated doses of umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in children with cerebral palsy. In addition, this study will contribute much needed data to the clinical trials community on the natural history of the motor function in CP over short-term (less than 1 year) time periods relevant to the conduct of clinical trials and assess the safety of AlloCB and hCT-MSC infusion in children with cerebral palsy.
Detailed description
This study is a phase I/II, prospective, randomized, open-label trial designed to determine the effect size of change in GMFM-66 score in subjects treated with hCT-MSC or allogeneic CB and assess the safety of repeated doses of hCT-MSC in children with cerebral palsy. Children ages 2-5 years with cerebral palsy due to hypoxic ischemic encephalopathy, stroke, or periventricular leukomalacia may be eligible to participate. All participants will ultimately be treated with an allogeneic cell product at some point during the study. Participants will be randomized to one of three arms: (1) the AlloCB arm will receive one allogeneic CB infusion at the baseline visit; (2) the MSC arm will receive three hCT-MSC infusions, one each at baseline, three months, and six months; (3) the natural history arm will not receive an infusion at baseline but will receive an allogeneic CB infusion at 12 months. Motor outcome measures will be assessed at baseline, six-months, and one-year time points. Safety will be evaluated at each infusion visit and remotely for an additional 12 months after the final visit. Duration of study participation will be 24 months from the time of baseline visit. Randomization to treatment arms will be stratified by GMFCS level at study entry and etiology of CP (Stroke vs. Other).
Interventions
BIOLOGICALInfusion of allogeneic umbilical cord blood
Subjects will receive a single infusion of allogeneic umbilical cord blood at the baseline visit.
BIOLOGICALInfusion of MSCs
Subjects will receive 3 infusions of MSCs (baseline, 3 months and 6 months).
Sponsors
The Marcus Foundation
Joanne Kurtzberg, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Every attempt will be made to blind the outcomes assessor.
Eligibility
Sex/Gender
ALL
Age
24 Months to 60 Months
Healthy volunteers
No
Inclusion criteria
1. Age ≥24 months and ≤60 months adjusted age at the time of enrollment. 2. Diagnosis: Unilateral or bilateral hypertonic cerebral palsy secondary to in utero or perinatal stroke/hemorrhage, hypoxic ischemic encephalopathy (including, but not limited to, birth asphyxia), and/or periventricular leukomalacia. 3. Performance status: Gross Motor Function Classification Score levels I - IV 4. Review of brain imaging (obtained as standard of care prior to study entry) does not suggest a genetic condition or brain malformation. 5. Legal authorized representative consent.
Exclusion criteria
1. Available qualified autologous cord blood unit. 2. Hypotonic or ataxic cerebral palsy without spasticity. 3. Autism and autistic spectrum disorders. 4. Hypsarrhythmia. 5. Legally blind 6. Intractable seizures causing epileptic encephalopathy. 7. Evidence of a progressive neurologic disease. 8. Has an active, uncontrolled systemic infection or documentation of HIV+ status. 9. Known genetic disease or phenotypic evidence of a genetic disease on physical exam. 10. Concurrent genetic or acquired disease or comorbidity(ies) that could require a future allogeneic stem cell transplant. 11. Requires ventilatory support, including home ventilator, CPAP, BiPAP, or supplemental oxygen. 12. Impaired renal or liver function as determined by serum creatinine \>1.5mg/dL and/or total bilirubin \>1.3mg/dL except in patients with known Gilbert's disease. 13. Possible immunosuppression, defined as WBC \<3,000 cells/mL or absolute lymphocyte count (ALC) \<1500 with abnormal T-cell subsets. 14. Patient's medical condition does not permit safe travel. 15. Previously received any form of cellular therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gross Motor Function Measure (GMFM-66) in Excess of Expected Change | Baseline to 12 months | GMFM-66 is used to evaluate gross motor function in children with cerebral palsy and is scored using a propriety software program called the Gross Motor Ability Estimator that produces an interval level continuous score ranging from 0 to 100. Higher scores indicate better motor function. The primary endpoint in this study was computed from the GMFM-66 score in three steps: 1) The observed change in motor function from Baseline to Month 12 was calculated (positive values indicate improvement, negative values indicate reduction, and zero indicates no change) for each participant; and 2) The expected change in motor function was determined for each participant based on published growth curves; and 3) The expected change in GMFM-66 was subtracted from the observed change to yield the final primary outcome. Positive values indicate a greater change than would be expected, zero indicates change as expected, and negative values indicate a smaller amount of change than would be expected. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | 12 months | The secondary endpoint of this study is the number of adverse events occurring over a 12-month period post-treatment with hCT-MSC or AlloCB. |
Countries
United States
Participant flow
Recruitment details
First participant randomized on April 10, 2018. Last participant randomized May 30, 2019. Single center study.
Participants by arm
| Arm | Count |
|---|---|
| Allogeneic Umbilical Cord Blood (AlloCB) Subjects will receive a single intravenous infusion of a maximum of 10x107/kg allogeneic umbilical cord blood (CB) cells
Infusion of allogeneic umbilical cord blood: Subjects will receive a single infusion of allogeneic umbilical cord blood at the baseline visit. | 31 |
| Cord Tissue Mesenchymal Stromal Cells (MSC) Subjects will receive three intravenous infusions of 2x106/kg human umbilical cord tissue cells (hCT-MSC), manufactured from allogeneic umbilical cord donors
Infusion of MSCs: Subjects will receive 3 infusions of MSCs (baseline, 3 months and 6 months). | 29 |
| Natural History, Then AlloCB Subjects will not receive any study product infusion until after the 12 month assessment. At the 12 month visit, they will receive an infusion of allogeneic umbilical cord blood cells so that all study participants will receive some type of cellular therapy.
Infusion of allogeneic umbilical cord blood: Subjects will receive a single infusion of allogeneic umbilical cord blood at the baseline visit. | 31 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Missed study visit due to pandemic restrictions | 7 | 5 | 6 |
| Overall Study | Protocol Violation | 4 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Allogeneic Umbilical Cord Blood (AlloCB) | Cord Tissue Mesenchymal Stromal Cells (MSC) | Natural History, Then AlloCB | Total |
|---|---|---|---|---|
| Age, Continuous | 3.47 years STANDARD_DEVIATION 0.96 | 3.53 years STANDARD_DEVIATION 0.88 | 3.55 years STANDARD_DEVIATION 0.84 | 3.52 years STANDARD_DEVIATION 0.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 27 Participants | 25 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized British Indian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Italian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 25 Participants | 24 Participants | 79 Participants |
| Region of Enrollment United States | 31 Participants | 29 Participants | 31 Participants | 91 Participants |
| Sex: Female, Male Female | 16 Participants | 9 Participants | 14 Participants | 39 Participants |
| Sex: Female, Male Male | 15 Participants | 20 Participants | 17 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 29 | 0 / 31 | 0 / 27 |
| other Total, other adverse events | 18 / 31 | 22 / 29 | 12 / 31 | 6 / 27 |
| serious Total, serious adverse events | 9 / 31 | 3 / 29 | 9 / 31 | 3 / 27 |
Outcome results
Primary
Change in Gross Motor Function Measure (GMFM-66) in Excess of Expected Change
GMFM-66 is used to evaluate gross motor function in children with cerebral palsy and is scored using a propriety software program called the Gross Motor Ability Estimator that produces an interval level continuous score ranging from 0 to 100. Higher scores indicate better motor function. The primary endpoint in this study was computed from the GMFM-66 score in three steps: 1) The observed change in motor function from Baseline to Month 12 was calculated (positive values indicate improvement, negative values indicate reduction, and zero indicates no change) for each participant; and 2) The expected change in motor function was determined for each participant based on published growth curves; and 3) The expected change in GMFM-66 was subtracted from the observed change to yield the final primary outcome. Positive values indicate a greater change than would be expected, zero indicates change as expected, and negative values indicate a smaller amount of change than would be expected.
Time frame: Baseline to 12 months
Population: Efficacy data not collected on Natural History participants after receiving allogeneic umbilical cord blood. Participants who did not complete the Month 12 visit are excluded.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Allogeneic Umbilical Cord Blood (AlloCB) | Change in Gross Motor Function Measure (GMFM-66) in Excess of Expected Change | 5.83 score on a scale |
| Cord Tissue Mesenchymal Stromal Cells (MSC) | Change in Gross Motor Function Measure (GMFM-66) in Excess of Expected Change | 4.27 score on a scale |
| Natural History | Change in Gross Motor Function Measure (GMFM-66) in Excess of Expected Change | 3.15 score on a scale |
Secondary
Number of Adverse Events
The secondary endpoint of this study is the number of adverse events occurring over a 12-month period post-treatment with hCT-MSC or AlloCB.
Time frame: 12 months
Population: Four participants randomized to the Natural History arm did not receive an infusion of AlloCB at Month12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Allogeneic Umbilical Cord Blood (AlloCB) | Number of Adverse Events | 30 adverse events |
| Cord Tissue Mesenchymal Stromal Cells (MSC) | Number of Adverse Events | 48 adverse events |
| Natural History | Number of Adverse Events | 16 adverse events |
| AlloCB After Natural History | Number of Adverse Events | 9 adverse events |