Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

ACE2 Gender Differences in Stroke With COVID-19 (ACEGENDER)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04766645
Recruitment Status : Not yet recruiting
First Posted : February 23, 2021
Last Update Posted : June 10, 2021
Sponsor:
Information provided by (Responsible Party):
Irene Giovanna Aprile, Fondazione Don Carlo Gnocchi Onlus

Brief Summary:

The new coronavirus SARS-CoV-2, causes the COVID-19 infection, which showed a form of neurovirulence involving the Central and peripheral Nervous Systems [Baig et al, 2020]. In a mouse model for human ACE2 expression, the virus entered the brain mainly through the olfactory bulb pathway [Netland et al, 2008], with an encephalic invasion uniformly lethal even with low viral doses and without lung involvement. The death of the animal was reasonably related to neuronal dysfunction/death in cardiorespiratory bone marrow centers, while the absence of ACE2 prevented severe encephalopathy.

Men has a highly frequency of severe and lethal COVID-19, and the observed gender difference could be related to the regulation of ACE2 receptor expression.

The ACE2 gene is encoded by a region of the X chromosome that escapes inactivation, so that women have an increased expression of this protein. The process of inactivation of the X chromosome includes DNA methylation with a decrease in the expression of genes that are affected by methylation. In This way an epigenetic mechanism could modulate the expression of ACE2 in a gender-specific way determining its levels and consequently its protective role.

Also in this regulatory context of ACE2 expression the role of microRNA (miRNA) could be very important. In fact, the untranslated 3' region (UTR) of ACE2 presents a binding sequence for miRNA miR-200c-3p that has been found at high levels of expression in cellular models infected with H5N1 influenza virus [Liu et al, 2017].

In addition, high plasma levels of miR-200c-3p were found in patients with severe pneumonia while ACE2 was reduced suggesting a regulatory role of this miRNA in ACE2 receptor expression [Liu et al, 2017]. Deficiency of 25 (OH)D is common among elderly and obese men (during winter and spring), highlighting the sex-specific difference observed in COVID-19 infection [La Vignera et al, 2020]. This vitamin, envolved in physical recovery [Siotto et al, 2019], and in the pathway of the renin angiotensin system, seems important to be assessed in ex-COVID-19 patients with stroke outcomes in admission and at the end of the rehabilitation process.

The study will consist in:

  • Epigenetic study: evaluation of methylation of ACE2 promoter and miR-200c-3p levels.
  • Biochemical analysis: the evaluation of levels of angiotensin II, ACE2 and Vitamin D.
  • Correlation between rehabilitative outcome and biological markers

Condition or disease Intervention/treatment
Neurologic Manifestations Device: Robotic assisted intervention Genetic: epigenetic analyses Diagnostic Test: biochemical analyses

Show Show detailed description

Layout table for study information
Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Gender Differences in Stroke With COVID-19: Epigenetic and Biochemical Study of ACE2 Receptor and Relationship With Rehabilitative Outcome
Estimated Study Start Date : June 10, 2021
Estimated Primary Completion Date : February 7, 2022
Estimated Study Completion Date : July 7, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Rehabilitation

Group/Cohort Intervention/treatment
Covid patients
Inpatients and outpatients admitted to the investigators' rehabilitation facility with covid symptoms
Device: Robotic assisted intervention
Conventional rehabilitation and Robotic treatment of the upper limb (30 sessions, 5 times a week) using a set of 4 robotic devices: Motore (Humanware); Amadeo, Diego, Pablo (Tyromotion). The training will include motor-cognitive exercises specifically selected to train spatial attention, vision and working memory, praxis, executive function, and speed of processing.

Genetic: epigenetic analyses
Epigenetic study: evaluation of methylation levels of ACE2 promoter and miR-200c-3p levels.

Diagnostic Test: biochemical analyses
Biochemical analysis: the evaluation of serum levels of angiotensin II, ACE2 and Vitamin D.




Primary Outcome Measures :
  1. Change in promoter methylation levels of ACE2 [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    Promoter methylation of ACE2 using pyrosequencing analysis with PyroMark Q24 (Qiagen, Germany).

  2. expression levels of miR-200c-3p in serum [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    expression levels of miR-200c-3p in serum using qRT-PCR (ThermoFisher)


Secondary Outcome Measures :
  1. serum levels of Angiotensin II, ACE2 and Vitamin D [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    serum levels of Angiotensin II, ACE2 and Vitamin D by ELISA assay tests (Bio-Rad)

  2. Change in Modified Barthel Index (BI) [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    The BI is designed to assess the ability of an individual with a neuromuscular or musculoskeletal disorder to care for him/herself. It ranges from 0 to 100, with a higher number meaning better performance in activities of daily living.

  3. Changes in the Montreal Cognitive Assessment (MoCA) [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Time to administer the MoCA is approximately 10 minutes. The maximum possible score is 30 points.

  4. Changes in the Cumulative Ilness Rating scale (CIRS) [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    The cumulative Illness Rating scale quantifies burden of disease in elderly patients (comorbidity scale). The cumulative score range from 0 to 56

  5. Change in Fugl-Meyer Assessment of Motor Recovery after Stroke for Upper Extremity portion (FMA-UL) [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    The FMA-UL is a stroke-specific, performance-based impairment index. It is designed to assess motor functioning, sensation and joint functioning in patients with post-stroke hemiplegia. The upper limb portion of the FMA-UL ranges from 0 (hemiplegia) to 66 points (normal upper limb motor performance).

  6. Numerical Rating Scale (NRS) [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    The Numeric Rating Scale (NRS) is the simplest and most commonly used numeric scale to rate the pain from 0 (no pain) to 10 (worst pain).

  7. Neuropathic Pain Four Questions (DN4) [ Time Frame: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1] ]
    The DN4 used to evaluate presence of neuropathic pain, and consist of a brief interview of four questions answered yes/no: two on what the patient has conceived and two during the exam for the evaluation of hypoesthesia to the touch or sting and the evaluation of allodynia with the skimming of the skin. For each 'yes' a point is assigned. The total score is given by the sum of the individuals. The cut off for the presence of neuropathic pain is '4'.

  8. change in Modified Ashworth Scale (MAS) [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    The MAS is a 6 point ordinal scale used for grading hypertonia in individuals with neurological diagnoses. A score of 0 on the scale indicates no increase in tone while a score of 4 indicates rigidity. Tone is scored by passively moving the individual's limb and assessing the amount of resistance to movement felt by the examiner.

  9. change in Motricity Index (MI) [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]

    The MI aims to evaluate lower limb motor impairment after stroke, administrated on both sides.

    Items to assess the lower limbs are 3, scoring from 0 to 33 each: (1) ankle dorsiflexion with foot in a plantar flexedposition (2) knee extension with the foot unsupported and the knee at 90° (3) hip flexion with the hip at 90° moving the knee as close as possible to the chin. (no movement: 0, palpable flicker but no movement: 9, movement but not against gravity :14, movement against gravity movement against gravity: 19, movement against resistance: 25, normal:33).


  10. hand grip strenght test [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    it is a test to measure the maximum isometric strength of the hand and forearm muscles

  11. pinch grip strenght test [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    A pinch grip is a form of precision grip whereby an object is pinched

  12. Change in Functional Ambulation Classification (FAC) [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    Functional Ambulation Classification is a functional walking test that evaluates ambulation ability. This 6-point scale assesses ambulation status by determining how much human support the patient requires when walking, regardless of whether or not they use a personal assistive device.

  13. change in 10 Meter Walk Test (10MWT) [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    This test will assess the patient's speed during gait. Patients will be asked to walk at their preferred maximum and safe speed. Patients will be positioned 1 meter before the start line and instructed to walk 10 meters, and pass the end line approximately 1 meter after. The distance before and after the course are meant to minimize the effect of acceleration and deceleration. Time will be measured using a stopwatch and recorded to the one hundredth of a second (ex: 2.15 s). The test will be recorded 3 times, with adequate rests between them. The average of the 3 times should be recorded.

  14. Change in Time Up And Go (TUG) [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    The Time Up And Go is a test used to assess mobility, balance, and walking in people with balance impairments. The subject must stand up from a chair (which should not be leant against a wall), walk a distance of 3 meters, turn around, walk back to the chair and sit down - all performed as quickly and as safely as possible. Time will be measured using a chronometer.

  15. Change in Six-Minute Walking Test (6MWT) [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    The 6MWT measures the distance a subject covers during an indoor gait on a flat, hard surface in 6 minutes, using assistive devices, as necessary. The test is a reliable and valid evaluation of functional exercise capacity and is used as a sub-maximal test of aerobic capacity and endurance. The minimal detectable change in distance for people with sub-acute stroke is 60.98 meters. The 6MWT is a patient self-paced walk test and assesses the level of functional capacity. Patients are allowed to stop and rest during the test. However, the timer does not stop. If the patient is unable to complete the test, the time is stopped at that moment. The missing time and the reason of the stop are recorded. This test will be administered while wearing a pulse oximeter to monitor heart rate and oxygen saturation, also integrated with Borg scale to assess dyspnea.

  16. Kinematic analysis [ Time Frame: [Time Frame: Baseline (T0), Treatment (6 weeks) (T1)] ]
    Kinematic information recorded during the administration of the Evaluation Task provided by Motore, based on a center-out point-to-point reaching activity.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with first ischemic stroke (of ischemic or hemorrhagic aetiology) in subacute phase (within six months after the acute event), hospitalized at the participating intensive-extensive rehabilitation centers will be included
Criteria

Inclusion Criteria:

  • stroke patients (hemorrhagic or ischemic) documented through Magnetic Resonance Imaging (MRI) or Computed Tomography (CT);
  • NeuroCOVID19 stroke patients with double nasopharyngeal swab negative after 24 hours for SARS-Cov2.
  • latency time within 6 months after stroke event;
  • sufficient cognitive and language skills to understand the instructions related to the administration of the assessment scales and to sign informed consent;

Exclusion Criteria:

  • behavioral and cognitive disorders that may interfere with the therapeutic activity;
  • other orthopaedic or neurological complications that may interfere with the rehabilitation protocol;
  • inability to understand and sign informed consent;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04766645


Contacts
Layout table for location contacts
Contact: IRENE APRILE, MD,PHD +390633085646 iaprile@dongnocchi.it
Contact: MARIACRISTINA SIOTTO, PHD +390633086552 msiotto@dongnocchi.it

Sponsors and Collaborators
Fondazione Don Carlo Gnocchi Onlus
Investigators
Layout table for investigator information
Principal Investigator: Irene Aprile, MD,PHD IRCCS Fondazione Don Carlo Gnocchi
Publications:

Layout table for additonal information
Responsible Party: Irene Giovanna Aprile, Md, PhD, Principal Investigator, Head of Rehabilitation Unit, Fondazione Don Carlo Gnocchi Onlus
ClinicalTrials.gov Identifier: NCT04766645    
Other Study ID Numbers: FDG_Acegender_2021
First Posted: February 23, 2021    Key Record Dates
Last Update Posted: June 10, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Irene Giovanna Aprile, Fondazione Don Carlo Gnocchi Onlus:
Stroke
rehabilitation
ACE2
methylation
VitaminD
Additional relevant MeSH terms:
Layout table for MeSH terms
Neurologic Manifestations
Nervous System Diseases