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

• ClinicalTrials.gov Identifier: NCT03252535
• Recruitment Status: Active, not recruiting
• First Posted: August 17, 2017
• Last Update Posted: December 13, 2019
• Sponsor: Azidus Brasil
• Collaborator: Cellavita Pesquisa Científica Ltda
• Information provided by (Responsible Party): Azidus Brasil

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Huntington Disease	Biological: Cellavita HD lower dose; Biological: Cellavita HD higher dose; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, 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).
• Primary Purpose: Treatment
• Official Title: Dose-Response Evaluation of the Investigational Product Cellavita HD After Intravenous Administration in Patients With Huntington's Disease
• Actual Study Start Date: January 15, 2018
• Estimated Primary Completion Date: January 2022
• Estimated Study Completion Date: April 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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 cycles every 120 days (total of 3 cycles).	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).; Other Name: cellular therapy, mesenchymal stem cells
Experimental: Cellavita HD Higher Dose; The participants randomized to this group 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).	Biological: 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 Name: cellular therapy, mesenchymal stem cells
Placebo Comparator: 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).	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).; Other Name: physiological solution without cells

Outcome Measures

Primary Outcome Measures :

1. Effective Dose [ Time Frame: monthly for fourteen months ]
   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.

Secondary Outcome Measures :

1. Clinical neurological worsening over the treatment [ Time Frame: monthly for fourteen months ]
   The clinical neurological worsening over the treatment will be evaluated by specific UHDRS domain.
2. BMI assessment [ Time Frame: monthly for fourteen months ]
   The BMI (Body Mass Index) will be assessed through the BMI profiles obtained during the treatment.
3. Risk of suicidal ideation [ Time Frame: monthly for fourteen months ]
   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).
4. CNS assessment [ Time Frame: baseline and one year later ]
   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.
5. Clinical Interview Based impression of Severity (CIBIS) [ Time Frame: monthly for fourteen months ]
   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.

Other Outcome Measures:

1. Safety administration of Cellavita HD product [ Time Frame: monthly for fourteen months ]
   Will be carefully evaluated from the periodical assessments including clinical, laboratory, and imaging exams, so that any change is properly recorded.
2. Prognosis of Huntington Disease [ Time Frame: baseline and one year later ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Brazil

Azidus Brasil Pesquisa Científica e Desenvolvimento Ltda.

Valinhos, São Paulo, Brazil, 13271-130

Sponsors and Collaborators

Azidus Brasil

Cellavita Pesquisa Científica Ltda

Investigators

• Principal Investigator: Joyce Macedo da Silva, MD; Azidus Brasil Scientific Research and Development Ltda

More Information

Publications:

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

• Responsible Party: Azidus Brasil
• ClinicalTrials.gov Identifier: NCT03252535 History of Changes
• Other Study ID Numbers: ADORE-DH; 52375916.1.0000.5412 ( Other Identifier: CAAE )
• First Posted: August 17, 2017
• Last Update Posted: December 13, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: It is believed that after the data analysis and presentation to the National Commission on Research Ethics, all data will become public.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Azidus Brasil:

Huntington disease; Stem cell therapy; Dental pulp stem cell

Additional relevant MeSH terms:

Huntington Disease; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Cognition Disorders; Neurocognitive Disorders; Mental Disorders