Dose-response Evaluation of the Cellavita HD Product in Patients With Huntington's Disease

Huntington Disease Clinical Trial

— ADORE-DH  

Official title:

Dose-Response Evaluation of the Investigational Product Cellavita HD After Intravenous Administration in Patients With Huntington's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03252535
• Other study ID #: ADORE-DH
• Secondary ID: 52375916.1.0000.
• Status: Completed
• Phase: Phase 2
• Start date: January 15, 2018
• Est. completion date: April 30, 2021

Study information

• Verified date: October 2022
• Source: Azidus Brasil
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: April 30, 2021
• Est. primary completion date: March 23, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Huntington Disease

Intervention

Biological:
• Cellavita 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).
• Cellavita 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).

Other:
• 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).

Locations

Country	Name	City	State
Brazil	Azidus Brasil Pesquisa Científica e Desenvolvimento Ltda.	Valinhos	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Azidus Brasil	Cellavita Pesquisa Científica Ltda

Country where clinical trial is conducted

Brazil, 

References & Publications (11)

Aleynik A, Gernavage KM, Mourad YSh, Sherman LS, Liu K, Gubenko YA, Rameshwar P. Stem cell delivery of therapies for brain disorders. Clin Transl Med. 2014 Jul 19;3:24. doi: 10.1186/2001-1326-3-24. eCollection 2014. Review. — View Citation

Barker RA, Mason SL, Harrower TP, Swain RA, Ho AK, Sahakian BJ, Mathur R, Elneil S, Thornton S, Hurrelbrink C, Armstrong RJ, Tyers P, Smith E, Carpenter A, Piccini P, Tai YF, Brooks DJ, Pavese N, Watts C, Pickard JD, Rosser AE, Dunnett SB; NEST-UK collaboration. The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease. J Neurol Neurosurg Psychiatry. 2013 Jun;84(6):657-65. doi: 10.1136/jnnp-2012-302441. Epub 2013 Jan 23. — View Citation

Bonelli RM, Wenning GK. Pharmacological management of Huntington's disease: an evidence-based review. Curr Pharm Des. 2006;12(21):2701-20. Review. — View Citation

de Almeida FM, Marques SA, Ramalho Bdos S, Rodrigues RF, Cadilhe DV, Furtado D, Kerkis I, Pereira LV, Rehen SK, Martinez AM. Human dental pulp cells: a new source of cell therapy in a mouse model of compressive spinal cord injury. J Neurotrauma. 2011 Sep;28(9):1939-49. doi: 10.1089/neu.2010.1317. Epub 2011 Aug 8. — View Citation

de Souza PV, Alves FB, Costa Ayub CL, de Miranda Soares MA, Gomes JR. Human immature dental pulp stem cells (hIDPSCs), their application to cell therapy and bioengineering: an analysis by systematic revision of the last decade of literature. Anat Rec (Hoboken). 2013 Dec;296(12):1923-8. doi: 10.1002/ar.22808. Epub 2013 Oct 15. Review. — View Citation

Fink KD, Deng P, Torrest A, Stewart H, Pollock K, Gruenloh W, Annett G, Tempkin T, Wheelock V, Nolta JA. Developing stem cell therapies for juvenile and adult-onset Huntington's disease. Regen Med. 2015;10(5):623-46. doi: 10.2217/rme.15.25. Review. — View Citation

Kaplan A, Stockwell BR. Therapeutic approaches to preventing cell death in Huntington disease. Prog Neurobiol. 2012 Dec;99(3):262-80. doi: 10.1016/j.pneurobio.2012.08.004. Epub 2012 Aug 28. Review. — View Citation

Kerkis I, Caplan AI. Stem cells in dental pulp of deciduous teeth. Tissue Eng Part B Rev. 2012 Apr;18(2):129-38. doi: 10.1089/ten.TEB.2011.0327. Epub 2011 Dec 28. Review. — View Citation

Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR; International Huntington's Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clin Genet. 2004 Apr;65(4):267-77. Erratum in: Clin Genet. 2004 Jul;66(1):81. — View Citation

Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, Scahill RI, Leavitt BR, Stout JC, Paulsen JS, Reilmann R, Unschuld PG, Wexler A, Margolis RL, Tabrizi SJ. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014 Apr;10(4):204-16. doi: 10.1038/nrneurol.2014.24. Epub 2014 Mar 11. Review. — View Citation

Weiss A, Träger U, Wild EJ, Grueninger S, Farmer R, Landles C, Scahill RI, Lahiri N, Haider S, Macdonald D, Frost C, Bates GP, Bilbe G, Kuhn R, Andre R, Tabrizi SJ. Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression. J Clin Invest. 2012 Oct;122(10):3731-6. doi: 10.1172/JCI64565. Epub 2012 Sep 17. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety administration of Cellavita HD product	Will be carefully evaluated from the periodical assessments including clinical, laboratory, and imaging exams, so that any change is properly recorded.	monthly for fourteen months
Other	Prognosis of Huntington Disease	This parameter will be evaluated by statistical comparison of NF-L (biological marker) results observed at baseline period and other analysed times. The results will be correlated to UHRDS scores.	baseline and one year later
Primary	Effective Dose	Consists of identifying the dose of the product Cellavita HD providing the best clinical response. It will be verified through the baseline Unified Huntington's Disease Rating Scale (UHDRS) score from the end of treatment (motor, cognitive, behavioral, functional capacity and independence domains). Additionally, also will be performed the combined score through the cUHDRS.	monthly for fourteen months
Secondary	Clinical neurological worsening over the treatment	The clinical neurological worsening over the treatment will be evaluated by specific UHDRS domain.	monthly for fourteen months
Secondary	BMI assessment	The BMI (Body Mass Index) will be assessed through the BMI profiles obtained during the treatment.	monthly for fourteen months
Secondary	Risk of suicidal ideation	Will be evaluated by suicidal domain from Hamilton Depression Scale (HAM-D). The classificatory punctuation may correspond to mild depression (score: 8 to 13), moderate depression (score: 19 - 22) and severe depression (score: > 23).	monthly for fourteen months
Secondary	CNS assessment	Will be evaluated by statistical comparison of the CNS assessment through magnetic resonance image at cortical thickness measurements, volumes of different brain structures, especially the basal ganglia, with special attention to caudate and metabolic changes identified in proton spectroscopy.	baseline and one year later
Secondary	Clinical Interview Based impression of Severity (CIBIS)	A general global assessment tool for disease severity that associates the impression of a medical interviewer with a patient / caregiver opinion. After observing the data obtained during the clinical interview, the interviewer records the appropriate score.	monthly for fourteen months