Huntington Disease
Conditions
Keywords
Huntington disease, Stem cell therapy, Dental pulp stem cell
Brief summary
Cellavita HD is a stem-cell therapy for Huntington's Disease. This is a prospective, phase II, single-center, randomized (2:2:1), triple-blind, placebo controlled study, with two test doses of Cellavita HD product.
Detailed description
This is a phase II dose-response study in which participants with HD will receive three intravenous injections of the investigational product or placebo (one every month for three months) a total of three cycles. The subjects will be randomized in 2: 2: 1 ratio for the groups G1: lower dose (1x10\^6 cells/weight range), G2: higher dose (2x10\^6 cells/weight range) or G3: placebo. To identify the dose of the product that will provide the best clinical response, motor assessment will be performed with UHDRS scale and improvement will be evaluated by correlating before and after treatment scores. Additionally, also will be performed the combined score through the cUHDRS. Secondary evidences of efficacy will be evaluated through the data of functional state, total functional capacity, functional independence, psychiatric symptoms and cognition from UHDRS scale. Additionally, related data to clinical worsening, change of Body Mass Index (BMI), risk of suicide attempt and neurological image improvement will be evaluated. Safety evaluation will included the incidence and classification of the adverse events experienced by the subjects during the study.
Interventions
BIOLOGICALCellavita HD lower dose
The participants will receive a total of 9 intravenous administrations of 1x10\^6 cells/weight range divided into three administrations per cycle. Each administration will occur every 30 days and cycles every 120 days (total of 3 cycles).
BIOLOGICALCellavita HD higher dose
The participants will receive a total of 9 intravenous administrations of 2x10\^6 cells/weight range divided into three administrations per cycle. Each administration will occur every 30 days and cycles every 120 days (total of 3 cycles).
OTHERPlacebo
The participants will receive a total of 9 intravenous administrations of placebo divided into three administrations per cycle. Each administration will occur every 30 days and cycles every 120 days (total of 3 cycles).
Sponsors
Cellavita Pesquisa Científica Ltda
Azidus Brasil
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The study drugs will be provided in identical packages to maintain the study masking. Neither the Investigator nor the study team will know which drug the subject is receiving. In addition, the external outcome evaluator will receive the results in a codified manner (concealed).
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Provide a written, signed and dated Informed Consent Form; 2. Male and female subjects aged ≥ 21 and ≤ 65 years; 3. Have a confirmatory diagnosis report (PCR) of Huntington's disease with a number of CAG repeats in chromosome 4 higher than or equal to 40, and lower than or equal to 50 (if the subject did not perform the exam and/or if he/she does not have an available result for this exam, a new exam must be performed); 4. A score of 5 points or higher for the motor evaluation of the UHDRS scale (Unified Huntington's Disease Rating Scale) at enrollment; 5. Score of 8 to 11 points for the functional capacity of the UHDRS scale at enrollment.
Exclusion criteria
1. Subject who participated in clinical trials protocols within the last twelve (12) months (Resolution CNS 251, August 7, 1997, item III, subitem J), unless, at the investigator's opinion, the subject would have a direct benefit from it; 2. Diagnosis of juvenile Huntington's disease; 3. Diagnosis of epilepsy; 4. Diagnosis of major cognitive disorder; 5. Active decompensated psychiatric illness; 6. Current or prior history of neoplasm; 7. Current history of gastrointestinal, hepatic, renal, endocrine, pulmonary, hematological, immunological, metabolic pathology or severe uncontrolled cardiovascular diseases; 8. Diagnosis of any active infection, whether viral, bacterial, fungal or caused by another pathogen; 9. Subject with contraindication to the exams performed in this study, for example, with pacemaker or surgical clip; Alcohol and drugs abuse (previously diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders - DSM V criteria); 10. Use of illegal drugs; 11. Tabagism; 12. Smoker or quit smoking for less than 6 months; 13. Positive result in one of the serum tests: HIV 1 and 2 (Anti-HIV-1,2), HTLV I and II, HBV (HBsAg, Anti-HBc), HCV (anti-HCV-Ab) and FTA-ABS (Treponema pallidum); 14. History of drug allergy, including to contrast agents used in imaging tests or bovine-derived products; 15. Using or expects to use immunosuppressant drugs or forbidden drugs (item 5.3) during the first three months after the first administration of the investigational product; 16. Any clinical change that the investigator considers a risk to subject's enrollment in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy by UHDRS-TMS | monthly for eleven months | The primary endpoint was the rate of change (slope) in Unified Huntington's Disease Rating Scale - Total Motor Score from V0 to V11 (minimum 0, the best; and maximum 124, the worst). For each participant, a regression line was fitted (Y = a + bx), where b represents the individual slope, reflecting the annualised rate of motor progression. A negative slope suggests improvement or slower decline; a positive slope indicates worsening. To compare treatment efficacy, the slopes were analysed using a Mixed Model for Repeated Measures (MMRM), which accounts for intra-subject variability and missing data. This approach allowed estimation and comparison of average slopes between each treated group and placebo, providing a robust measure of motor function trajectory over time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy by UHDRS-TFC | monthly for eleven months | Assessed by the rate of change (slope) from V0 to V11 in the UHDRS-TFC. The response of each participant or means of all participants was evaluated by the slopes of each regression line of UHDRS-TFC determined as follows: The equation describes the regression line: Y = a + bx, where: * Y is the dependent variable. * a is the constant that represents the intersection of the line with the vertical axis. * b is the angular coefficient, that is, the slope. * x is the independent variable. Therefore, the 'b' value represents the slope of the straight line that best fits the values collected from the baseline (V0) to the value of V11, using the least squares method. This slope corresponds to the estimated annualized individual variation of UHDRS-TFC during the given period. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exposure to NestaCell (Former Cellavita HD) Product | eleven months | Number of administrations of NestaCell (Former Cellavita HD) and Placebo |
Countries
Brazil
Participant flow
Pre-assignment details
Of 49 enrolled participants, 35 met the inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Nestacell (Former Cellavita HD) Lower Dose The participants randomized to this group will receive a total of 9 intravenous administrations of 1x10\^6 cells/weight range divided into three administrations per cycle. Each administration will occur every 30 days and cycle every 120 days (a total of 3 cycles).
NestaCell lower dose: The participants will receive a total of 9 intravenous administrations of 1x10\^6 cells/weight range divided into three administrations per cycle. Each administration will occur every 30 days and cycle every 120 days (a total of 3 cycles). | 14 |
| Nestacell (Former Cellavita HD) Higher Dose The participants randomized to this group will receive a total of 9 intravenous administrations of 2 × 10\^6 cells/weight range, divided into three administrations per cycle. Each administration will occur every 30 days and cycle every 120 days (a total of 3 cycles).
NestaCell higher dose: The participants will receive a total of 9 intravenous administrations of 2x10\^6 cells/weight range divided into three administrations per cycle. Each administration will occur every 30 days and cycle every 120 days (a total of 3 cycles). | 14 |
| Placebo Group The participants randomized to this group will receive a total of 9 intravenous administrations divided into three administrations per cycle. Each administration will occur every 30 days and cycles every 120 days (total of 3 cycles).
Placebo: The participants will receive a total of 9 intravenous administrations of placebo divided into three administrations per cycle. Each administration will occur every 30 days and cycles every 120 days (total of 3 cycles). | 7 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Met discontinuation criteria | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Nestacell (Former Cellavita HD) Lower Dose | Total | Placebo Group | Nestacell (Former Cellavita HD) Higher Dose |
|---|---|---|---|---|
| Age, Continuous | 51.6 years STANDARD_DEVIATION 9.4 | 48.7 years STANDARD_DEVIATION 9.2 | 50.9 years STANDARD_DEVIATION 9.7 | 43.7 years STANDARD_DEVIATION 8.5 |
| BMI | 24.4 Kg/m^2 STANDARD_DEVIATION 4.5 | 25.3 Kg/m^2 STANDARD_DEVIATION 4.8 | 25.0 Kg/m^2 STANDARD_DEVIATION 4.4 | 26.4 Kg/m^2 STANDARD_DEVIATION 5.5 |
| CAG repeat <44 | 9 Participants | 20 Participants | 4 Participants | 7 Participants |
| CAG repeat >=44 | 5 Participants | 15 Participants | 3 Participants | 7 Participants |
| CAP scale | 106.7 units on a scale STANDARD_DEVIATION 18.6 | 105.0 units on a scale STANDARD_DEVIATION 14 | 110.7 units on a scale STANDARD_DEVIATION 12 | 97.5 units on a scale STANDARD_DEVIATION 11.5 |
| Height | 1.63 meters STANDARD_DEVIATION 0.08 | 1.63 meters STANDARD_DEVIATION 0.08 | 1.66 meters STANDARD_DEVIATION 0.06 | 1.61 meters STANDARD_DEVIATION 0.1 |
| Race/Ethnicity, Customized Black | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiracial | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 22 Participants | 4 Participants | 9 Participants |
| Region of Enrollment Brazil | 14 participants | 35 participants | 7 participants | 14 participants |
| Sex: Female, Male Female | 7 Participants | 18 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 5 Participants | 5 Participants |
| UHDRS Total Functional Capacity | 8.1 units on a scale STANDARD_DEVIATION 2.1 | 7.7 units on a scale STANDARD_DEVIATION 2 | 6.7 units on a scale STANDARD_DEVIATION 1.4 | 8.4 units on a scale STANDARD_DEVIATION 2.6 |
| UHDRS Total Motor Score | 43.6 units on a scale STANDARD_DEVIATION 23.8 | 34.1 units on a scale STANDARD_DEVIATION 14.4 | 38.0 units on a scale STANDARD_DEVIATION 7.5 | 20.7 units on a scale STANDARD_DEVIATION 11.8 |
| Weight | 65.5 Kg STANDARD_DEVIATION 14 | 67.8 Kg STANDARD_DEVIATION 14.2 | 69.3 Kg STANDARD_DEVIATION 14 | 68.7 Kg STANDARD_DEVIATION 14.5 |
| Years of symptoms | 10.1 years STANDARD_DEVIATION 3.6 | 9.2 years STANDARD_DEVIATION 3 | 10.1 years STANDARD_DEVIATION 3.2 | 7.4 years STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 7 |
| other Total, other adverse events | 12 / 14 | 12 / 14 | 7 / 7 |
| serious Total, serious adverse events | 1 / 14 | 0 / 14 | 0 / 7 |
Outcome results
Primary
Efficacy by UHDRS-TMS
The primary endpoint was the rate of change (slope) in Unified Huntington's Disease Rating Scale - Total Motor Score from V0 to V11 (minimum 0, the best; and maximum 124, the worst). For each participant, a regression line was fitted (Y = a + bx), where b represents the individual slope, reflecting the annualised rate of motor progression. A negative slope suggests improvement or slower decline; a positive slope indicates worsening. To compare treatment efficacy, the slopes were analysed using a Mixed Model for Repeated Measures (MMRM), which accounts for intra-subject variability and missing data. This approach allowed estimation and comparison of average slopes between each treated group and placebo, providing a robust measure of motor function trajectory over time.
Time frame: monthly for eleven months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nestacell (Former Cellavita HD) Lower Dose | Efficacy by UHDRS-TMS | -1.23 score on a scale/year | Standard Error 0.84 |
| Nestacell (Former Cellavita HD) Higher Dose | Efficacy by UHDRS-TMS | 0.84 score on a scale/year | Standard Error 0.9 |
| Placebo Group | Efficacy by UHDRS-TMS | 8.91 score on a scale/year | Standard Error 1.11 |
Secondary
Efficacy by UHDRS-TFC
Assessed by the rate of change (slope) from V0 to V11 in the UHDRS-TFC. The response of each participant or means of all participants was evaluated by the slopes of each regression line of UHDRS-TFC determined as follows: The equation describes the regression line: Y = a + bx, where: * Y is the dependent variable. * a is the constant that represents the intersection of the line with the vertical axis. * b is the angular coefficient, that is, the slope. * x is the independent variable. Therefore, the 'b' value represents the slope of the straight line that best fits the values collected from the baseline (V0) to the value of V11, using the least squares method. This slope corresponds to the estimated annualized individual variation of UHDRS-TFC during the given period.
Time frame: monthly for eleven months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nestacell (Former Cellavita HD) Lower Dose | Efficacy by UHDRS-TFC | -0.29 score on a scale/year | Standard Error 0.18 |
| Nestacell (Former Cellavita HD) Higher Dose | Efficacy by UHDRS-TFC | 0.73 score on a scale/year | Standard Error 0.18 |
| Placebo Group | Efficacy by UHDRS-TFC | -0.89 score on a scale/year | Standard Error 0.26 |
Other Pre-specified
Exposure to NestaCell (Former Cellavita HD) Product
Number of administrations of NestaCell (Former Cellavita HD) and Placebo
Time frame: eleven months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nestacell (Former Cellavita HD) Lower Dose | Exposure to NestaCell (Former Cellavita HD) Product | 9.0 number os adminstrations | Standard Deviation 0 |
| Nestacell (Former Cellavita HD) Higher Dose | Exposure to NestaCell (Former Cellavita HD) Product | 8.4 number os adminstrations | Standard Deviation 1.5 |
| Placebo Group | Exposure to NestaCell (Former Cellavita HD) Product | 9.0 number os adminstrations | Standard Deviation 0 |