Within Subject Crossover Study of Cognitive Effects of Neflamapimod in Early-Stage Huntington Disease

• ClinicalTrials.gov Identifier: NCT03980938
• Recruitment Status: Terminated
• First Posted: June 10, 2019
• Results First Posted: April 6, 2022
• Last Update Posted: April 6, 2022
• Sponsor: EIP Pharma Inc
• Collaborator: Voisin Consulting, Inc.
• Information provided by (Responsible Party): EIP Pharma Inc

Study Description

Brief Summary:

This is a double-blind, placebo-controlled 2-period 10-week treatment within-subject crossover study of neflamapimod in early-stage Huntington disease (HD). The primary objective is to determine whether neflamapimod can reverse hippocampal dysfunction in patients with early-stage HD, as assessed by the virtual water-maze-test for evaluating spatial learning and selected tests on the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Condition or disease	Intervention/treatment	Phase
Huntington Disease	Drug: neflamapimod; Other: Placebo	Phase 2

Detailed Description:

The study was designed as within-subject crossover study. However, due to the Covid19 lockdowns and restrictions on clinical research, and only one subject entered the second crossover period. As a result, the baseline and outcomes are reported by the actual treatment received in the subjects during what would have been the first treatment period, i.e. placebo or neflamapimod treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled Two-Period 10-Week Treatment Within-Subject Crossover Study Of Cognitive Effects Of Neflamapimod in Early-Stage Huntington Disease (HD)
• Actual Study Start Date: July 8, 2019
• Actual Primary Completion Date: October 15, 2020
• Actual Study Completion Date: October 15, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: neflamapimod first; neflamapimod in Treatment Period 1, placebo in Treatment Period 2 neflamapimod: 40 mg neflamapimod hard gelatin capsules, taken twice daily with food. Placebo: hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.	Drug: neflamapimod; 40 mg neflamapimod capsule; Other Name: VX-745; Other: Placebo; matching placebo capsule
Placebo Comparator: placebo first; placebo in Treatment Period 1, neflamapimod in Treatment Period 2 Placebo: hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food. neflamapimod: 40 mg neflamapimod hard gelatin capsules, taken twice daily with food.	Drug: neflamapimod; 40 mg neflamapimod capsule; Other Name: VX-745; Other: Placebo; matching placebo capsule

Outcome Measures

Primary Outcome Measures :

1. Change in Latency During the Learning Phase of Virtual Morris Water Maze Test (vMWM) [ Time Frame: Baseline and 10 Weeks ]
   Change from baseline of latency during the learning phase of vMWM (hidden platform training) in the neflamapimod first group compared to placebo first group

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Men and women age 30 to 70 years, inclusive.
2. Willing and able to provide informed consent.

3. Must have genetically confirmed HD and identified cognitive deficits:

   1. Stage 1, as defined by Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) score >10, and,
   2. CANTAB Paired Associate Learning Total Adjusted Error Score of >16.
4. Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
5. No history of learning difficulties that may interfere with the subject's ability to complete the cognitive tests.

Exclusion Criteria:

1. A profile of impairment that is not consistent with HD.
2. Diagnosis of any other ongoing central nervous system condition other than HD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and Parkinson's disease.
3. Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
4. Ongoing major and active psychiatric disorder, moderate to severe depressive symptoms, and or other concurrent medical condition that, in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
5. Diagnosis of alcohol or drug abuse within the previous 2 years.
6. Poorly controlled clinically significant medical illness, such as hypertension (blood pressure >180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 6 months; uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude treatment with p38 mitogen activated protein (MAP) kinase inhibitor and/or assessment of drug safety and efficacy.
7. Anemia with a hemoglobin ≤10 g/dL, clinically significant thyroid function abnormality, electrolyte abnormalities.
8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × the upper limit of normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized Ratio (INR) >1.5.
9. Known human immunodeficiency virus; or active hepatitis B or hepatitis C virus infection; evidence of active or latent tuberculosis.
10. Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
11. History of previous neurosurgery to the brain.
12. Female subjects who are pregnant or breast-feeding.
13. Male subjects with female partners of child-bearing potential who are unwilling or unable to adhere to contraception requirements specified in the protocol (see Section 5.8).
14. Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingo-oophorectomy and are not willing or unable to adhere to contraceptive requirements specified in the protocol (see Section 5.8).
15. Requires concomitant use of cytochrome P450 (CYP) 3A4 inhibitors or anti-tumor necrosis factor-alpha therapies during study participation.
16. Known allergy to any ingredient of the trial medication or placebo.

Contacts and Locations

Locations

United Kingdom

John Van Geest Centre for Brain Repair

Cambridge, United Kingdom, CB2 0PY

Sponsors and Collaborators

EIP Pharma Inc

Voisin Consulting, Inc.

Investigators

• Study Director: John Alam, MD; EIP Pharma

  Study Documents (Full-Text)

Documents provided by EIP Pharma Inc:

Study Protocol  [PDF] July 30, 2019

Statistical Analysis Plan  [PDF] February 3, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tormahlen NM, Martorelli M, Kuhn A, Maier F, Guezguez J, Burnet M, Albrecht W, Laufer SA, Koch P. Design and Synthesis of Highly Selective Brain Penetrant p38alpha Mitogen-Activated Protein Kinase Inhibitors. J Med Chem. 2022 Jan 27;65(2):1225-1242. doi: 10.1021/acs.jmedchem.0c01773. Epub 2021 May 11.

• Responsible Party: EIP Pharma Inc
• ClinicalTrials.gov Identifier: NCT03980938
• Other Study ID Numbers: EIP19-NFD-401
• First Posted: June 10, 2019
• Results First Posted: April 6, 2022
• Last Update Posted: April 6, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

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