NeuroEPO in patients with Parkinson disease stage II-III

General information

Section to complete general information about the trial: scientific and public title, protocol identifiers, sponsors and Source(s) of Monetary or Material Support.

Acronym of Public Title:

mAkEUP

Scientific title:

Assessing the efficacy and safety of nasal NeuroEpo management in Patients disease with Parkinson stage II-III

Acronym of Scientific Title:

mAkEUP

Secondary indentifying numbers:

Not applicable

Issuing authority of the secondary identifying numbers:

169

Source(s) of monetary or material support:

Center of Molecular Immunology (CIM)Ministry of Public Health (MINSAP)

Authorization for beginning

Section to complete information about the regulatory approval of clinical trial: regulatory agency name, approval date and reference number in the agency.

Regulatory instance to authorize the initiation of the study:

Center for State Control of Drugs, Medical Devices and Equipment (CECMED)

Authorization date :

09/06/2018

Reference number:

0607/05.007.17BA

Principal investigator

Section to complete information about Email address, telephone number and postal address of the Principal Investigator.

First name:

Ivonne

Last name:

Pedroso Ibañez

Medical Specialty :

First degree specialist in Neurology

Affiliation:

International Center of Neurologic Restoration (CIREN)

Postal address:

Ave. 25 No. 15805, e/ 158 y160. Cubanacan, Playa

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+53-72736777

Email address:

ivon@neuro.ciren.cu [1]

Clinical sites to participate

Section to complete the data related to the clinical sites involved in the trial: site and responsible investigator for every site.

Countries of recruitment:

Cuba

Clinical sites:

Havana, National Institute of Neurology, MD. Alexis Soto Lavastida, Second degree specialist in Neurology

Research ethics committees:

International Center of Neurologic Restoration (CIREN), February 01, 2017

Recruitment status

Section to complete information about the recruitment status and the date of first enrolment subject

Recruitment status:

Complete

Date of first enrollment:

08/12/2017

Health condition and Intervention

Section to complete information about the primary medical condition(s) or problem(s) studied and, a characteristics of the intervention(s).

Health condition(s) or Problem(s) studied:

Parkinson's disease stage II-III

Health condition(s) code:

Parkinson Diseases

Parkinsonian Disorders

Basal Ganglia Diseases

Brain Diseases

Central Nervous System Diseases

Nervous System Diseases

Movement Disorders

Neurodegenerative Diseases

Intervention(s):

Group A (experimental): 0.5 mg NeuroEPO by intranasal route, 3 times a week for 4 weeks (induction period) and, then continue with 1mg weekly for 20 weeks (maintenance period). Group B (experimental): 1.0 mg NeuroEPO by intranasal route, 3 times a week for 4 weeks (induction period) and then, continue with the same doses weekly for 20 weeks (maintenance period). Group C (control): Placebo. This group will be divide in two equal subgroups (one for each experimental group). The patients will receive the same doses, schema and administration route.

Intervention code:

Erythropoietin

Neuroprotective Agents

Administration, Intranasal

Placebos

Intervention keyword:

NeuroEPO

Outcomes and Timepoint

Section to complete information about primary and secondary outcomes including. It includes the metric or method of measurement used and, the time point for every outcome.

Primary outcome(s):

Total UPDRS Value (UPDRS scale). Measuring time: 9 months.

Key secondary outcomes:

Related to eficacy 1. UPDRS motor. measure by UPDRS III. Measuring time: 0, 6, 9 months 2. Daytime mobility fluctuations: measured by self-report. Measure by: Presence of on/off (on and off) dyskinesias (yes/no), dystonias (score), paradoxical fluctuations (score). Measuring time: 0, 6, 9 months 3. Total dose of dopaminergic stimulation. Measure by percentage. Measuring time: in each administration of the product. 4. Cognitive impairment. Measured by the DRS (Dementia Rating Scale) by Mattis. Measuring time:: 0, 9 months 5. Mental flexibility. Measured by the Trail Test (TMT). Measuring time: 0, 9 months 6. Working Memory. Measured by the TMT. Measuring time: 0, 9 months 7. Motor response rate. Measured by the TMT. Measuring time: 0, 9 months 8. Sustained attention. Measured by subtest 2 of the WAIS III Working Memory Index. Measuring time: 0, 9 months 9. Working memory. Measured by subtest 2 of the WAIS III Working Memory Index. Measuring time: 0, 9 months 10. Phonological verbal fluency. Measured by the Verbal Fluency Test (FAST). Measuring time: 0, 9 months 11. Semantic verbal fluency. Measured by FAST. Measuring time: 0, 9 months 12. Ability to alternate mental categories. Measured by FAST. Measuring time: 0, 9 months 13. Executive function. Measured by Litvan Frontal Assessment Battery (FAB). Measuring time: 0, 9 months 14. Selective attention (Measured by Stroop test). Measuring time:: 0, 9 months 15. Focused attention (Measured by Stroop test). Measuring time: 0, 9 months 16. Visuoconstructive function (Measured by Fig. De Rey). Measuring time: 0, 9 months 17. Visual memory (Measured by Fig. Of Rey). Measuring time:: 0, 9 months 18. Level of anxiety. Measured by the HADS (Hospital Anxiety and Depression Scale) Hospital Anxiety and Depression Scale. Measuring time: 0, 9 months 19. Level of depression. Measured by HADS. Measuring time: 0, 9 months Related to safety: 20. Adverse Events-AE (Severity of AE (serious or not), Type of AE (accordint to Regulation 45/2007 CECMED), Intensity of AE (mild, moderate, serious), Causality relationship (Very likely, Likely, possible, unlikely, unrelated or non-evaluable), Attitude about the drug (No change, dose reduction, temporary interruption of treatment, definitive discontinuation of treatment), Outcome (Reversible effect, irreversible effect, death, loss of patient follow-up)). Measuring time: in each evaluation at 6 and 9 months and in each administration of the product. 21. Laboratory test (Hemoglobin (Normal, abnormal), Hematocrit (Normal, abnormal), Platelet count (Normal, abnormal), Leukocyte count (Normal, abnormal), Glycemia (Normal, abnormal), TGO (Normal, abnormal), TGP (Normal, abnormal), GGT (Normal, abnormal), Creatinine, (Normal, abnormal), uric acid (Normal, abnormal), urea (normal, abnormal)). Measuring time: 0, 6 and 9 months. 22. Blood pressure (mm/Hg). Measuring time: in each evaluation at 0, 6 and 9 months and in each administration of the product.

Selection criterias

Section to complete information about the inclusion and exclusion criteria for participant selection, including age and gender.

Gender:

Male/Female

Minimum age:

18 years

Maximum age:

None

Inclusion criteria:

1. Patients with Parkinson's disease, who meet the diagnostic criteria of BBL and stage II-III according to Hoehn and Yahr scale. 2. Patients older than 18 years. 3. One or more years of evolution of motor symptoms. 4. Good response to dopaminergic stimulation. 5. Acceptable general health status, not previous polygllobulia (Hto equal or lower than 50). 6. Patients who consent to participate in the study by signing the informed consent model.

Exclusion criteria:

1. Negative patient to participate in the study. 2. Presence of signs indicative of cognitive deterioration or psychiatric complications at the time of study. 3. Presence of accidents or other diseases during the therapeutic period that disqualify the patient to clinical trial. 4. Patients with known hypersensitivity to any component of the formulation. 5. Patients who are pregnant or breastfeeding. 6. Patients of childbearing potential not using contraceptive methods. 7. Patients with uncontrolled hypertension (systolic pressure mayor 180 mmHg and / or diastolic pressure mayor 120 mmHg). 8. Patients receiving treatment with immunosuppressants, androgens or anabolic steroids in the month prior to inclusion. 9. Patients with haematological diseases: sickle cell, myelodysplastic syndromes, coagulation disorders or active bleeding. 10. Patients with severe hyperparathyroidism. 11. Patients diagnosed with malignant tumor or anticancer therapy. 12. Patients with decompensated psychiatric illness. 13. Patients with alcoholism or drug addiction in the two years prior to the evaluation for inclusion.

Type of population:

Adults

Type of participant:

Patients

Study design

Section to complete information about the characteristics of the study design.

Type study:

Interventional

Purpose:

Treatment

Allocation:

Randomized controlled trial

Masking:

Double Blind

Control group:

Placebo

Study design:

Parallel

Phase:

2-3

Target sample size:

102

Contact for public queries

Section to complete information about Email address, telephone number and postal address of the contact who will respond to general queries, including information about current recruitment status

First Name:

Leslie

Last Name:

Perez Ruiz

Specialty:

Bachelor in Pharmaceutical Sciences

Affiliation:

Center of Molecular Immunology (CIM)

Postal Address:

Calle 216, esquina 15. Atabey, Playa

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+537-2143202 +5372143202

Email :

leslie@cim.sld.cu [2]

Contact for scientific queries

Section to complete information about Email address, telephone number and postal address of the contact who will respond to scientific queries.

First Name:

Ivonne

Last Name:

Pedroso Ibannez

Specialty:

First degree specialist in Neurology

Affiliation:

International Center of Neurologic Restoration (CIREN)

Postal Address:

Ave. 25 No. 15805, e/ 158 y160. Cubanacan, Playa

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+53-72736777 ext 722

Email :

ivon@neuro.ciren.cu [1]

About study completion

Section to complete the data related to the study completion.

Final enrolment number:

102

Study completion date:

06/04/2021

Date of available results:

31/07/2023

Results Study

Section to complete the data related to the summarized results.

Summary study:

EFFICIENCY RESULTS The study hypothesis predicted a neurological recovery, expecting the decrease in the UPDRS-MDS to be at least 3 points lower than the control group. This hypothesis was not fulfilled, even when there was improvement (decrease in the total UPDRS-MDS score in all groups). These started from a UPDRS-MDS median that ranged in each group from 67, 71 and 72 points for NeuroEPO 0.5, 1.0 and placebo, respectively, with a p-value of 0.809. At 6 months no significant differences were detected between the groups; the median of UPDRS-MDS in this evaluation is reported by group of 43, 44 and 47 points respectively, with a p-value of 0.772. At 9 months in the groups treated with neuroEPO no statistically significant changes were detected showing the following median values 48, 45 and 48 points respectively and a p-value of 0.820. Comparing initial values - 6 months there are no significant differences between the groups treated with neuroEPO and the Placebo group. At 9 months the trend continues towards a decrease in the values of the scale, with median values of 23, 20 and 21 points respectively and a p-value of 0.993. The magnitude of the observed differences was 0.0 and 0.4 points (UPDRS-MDS value) in the 0.5 mg and 1.0 mg groups vs. placebo, respectively. It is considered that the main cause, despite the fact that the group treated with neuroEPO achieved the improvement in the UPDRS-MDS score, does not show significant differences vs. the placebo group, is attributed to the Placebo Effect. The neuroEPO molecule is proposed as a neuroprotector, not as an antiparkinsonian drug, with which the placebo effect may even exceed its symptomatic effect in patients with PD, as was demonstrated in this study. All actions that induce the expectation of benefit can act like a placebo, positively impacting the brain circuits in these patients. Placebo-associated improvement in PD has been found to be independent of gender, age, disease duration, and baseline disability score as measured by the UPDRS-MDS. The challenges in studying the placebo effect in clinical trials is the use of biomarkers to predict it. With respect to Neuropsychology, the analysis carried out using the measures of central tendency (mean, median, standard deviation, and percentages by categories) for the comparison between the three groups in time; 0 and 9 months, as well as the final-initial difference in each group, A and B with respect to the control group C, did not show significant differences. All the patients improved. In the Connectivity analysis, the three groups showed a decrease in global synchronization for the alpha frequency band and an increase in theta frequency with different topography. Group A (0.5mg) showed a very slight increase in synchronization for the beta and theta frequency bands, the latter located towards the frontal and central regions of the right hemisphere. Group B (1.0mg) showed similar results to group A, noting a slight increase in synchronization in addition to the delta frequency and in group C (placebo) the marked increase in synchronization stands out for the theta frequency band, which unlike group A showed a global topography, and a decrease for the beta, alpha and delta frequencies in the patients after having received the treatment (permutation test p<0.05 for all cases). Functional connectivity by EEG demonstrated the structuring of the functional network in groups A and B after treatment, which evidenced a change in the organization dependent on the delta band. This result could suggest the changes in the brain networks in groups A and B. The modifications found in group C point to a disruption of the functional network in terms of segregation and integration that involves the delta, theta and alpha bands. Functional connectivity translates changes in functional brain networks without defining improvement or worsening. It needs to be integrated into clinical outcomes. Despite not fulfilling the hypothesis raised from the clinical point of view, in practice total permanence in the protocol of the research subjects was observed, as well as motor changes in gait, the ability to go up and down the stairs in the place research, increased independence, the family commented on the participation of patients in home tasks and activities. It was always striking that some improved more than others and that the parameters evolved differently in each patient. Non-motor symptoms also improved since in this disease there are multiple complaints from the mourners and in the group that constituted the study sample it was found that complaints due to insomnia and constipation disappeared, these changes were the most frequent in general. . Faced with this evidence, it was decided to carry out other evaluations with the Univariate analysis and the Causality analysis that demonstrated motor and non-motor results in the study groups with significant differences in relation to the placebo group. SAFETY RESULTS Intranasally administered neuroEPO is safe for patients with Hoehn and Yahr stage II III Parkinson's disease, the safety analysis in the study showed that neuroEPO treatment was well tolerated and safe. Twenty-six AEs were recorded, those classified as mild predominated, with an unrelated causal relationship and did not lead to changes in treatment. The most frequent AEs were: nasal stinging sensation, hyperuricemia, decreased hemoglobin and hematocrit. The AE nasal burning in one patient was considered related to the use of the study drug and occurred in the neuroEPO 1 mg group. CONCLUSIONS - NeuroEPO shows no evidence of efficacy in patients with Hoehn and Yahr stage II-III Parkinson's disease as measured by total UPDRS-MDS. The final median in the UPDRS-MDS evaluation in both PP and ITT and in the three treatment groups decreased with respect to the initial evaluation, thus decreasing the values over time, but did not show statistically significant differences in the comparison between groups. - The neuroEPO molecule is proposed as a neuroprotective agent, not as an antiparkinsonian drug, with which the placebo effect may even exceed its symptomatic effect in patients with PD. The univariate and causal analysis shows efficacy in the motor and cognitive variables in the sample of patients with Hoehn and Yahr stage II III Parkinson's disease. - NeuroEPO is safe in patients with Hoehn and Yahr stage II III Parkinson's disease, taking into account that the adverse events related to the product were mild, reversible and did not compromise the lives of the patients. - Motor, cognitive and affective parameters in PD patients treated with neuroEPO and with placebo all improved in all three treatment groups. - Functional connectivity by EEG shows a structuring of the functional network in groups A and B while in group C they point to a breakdown of the functional network.

Registration and Update

Section to complete information about the name of Primary Registry, date of registration and the unique ID number assigned by the registry (RPCEC).

Primary registry:

RPCEC

Unique ID number:

RPCEC00000233

Date of Registration in Primary Registry:

01/02/2017

Record Verification Date:

2023/07/31

Next update date:

2024/07/31

Link to the spanish version:

Click here [3]