Phase 1 Dose Escalation and PK Study of Cu(II)ATSM in ALS/MND

• ClinicalTrials.gov Identifier: NCT02870634
• Recruitment Status: Completed
• First Posted: August 17, 2016
• Last Update Posted: March 17, 2020
• Sponsor: Collaborative Medicinal Development Pty Limited
• Information provided by (Responsible Party): Collaborative Medicinal Development Pty Limited

Study Description

Brief Summary:

Multicenter, open-label , single and multiple dose-escalation and pharmacokinetic study

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis; Motor Neuron Disease	Drug: Cu(II)ATSM	Phase 1

Detailed Description:

Multicenter, open-label, phase 1 study of Cu(II)ATSM administered orally to patients wit amyotrophic lateral sclerosis/motor neuron disease. The study will be conducted in three phases. In the first two phases, dose cohorts of six patients each will participate in a single dose pharmacokinetic study followed by a 28-day repeated daily dose study to establish the recommended phase 2 dose (RP2D). The first dose cohort will be treated at 3 mg/day; planned dose escalations are 6, 12, 24, and 48 mg/day, subject to observed safety assessments. In the third phase of the study, participants will be treated at the RP2D to confirm tolerability and assess preliminary evidence of efficacy.

In both the dose escalation and expansion cohorts, once the first 28 days of treatment and assessments are completed, at the discretion of the investigator a patient may continue to receive Cu(II)ATSM treatment for a maximum of six 28-day treatment cycles.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Single and Multiple Dose Escalation and Pharmacokinetic Study of Cu(II)ATSM Administered Orally to Patients With Amyotrophic Lateral Sclerosis/Motor Neuron Disease
• Actual Study Start Date: November 16, 2016
• Actual Primary Completion Date: October 30, 2019
• Actual Study Completion Date: January 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cu(II)ATSM; Cu(II)ATSM capsules, administered orally once daily	Drug: Cu(II)ATSM; copper-containing synthetic small molecule; Other Name: diacetylbis(N(4)-methylthiosemicarbazonato) copper(II)

Outcome Measures

Primary Outcome Measures :

1. recommended phase 2 dose as determined by the number of participants at each dose level with dose limiting toxicities [ Time Frame: 24 months ]

Secondary Outcome Measures :

1. Treatment-related change in disease severity by ALS Functional Rating Scale - Revised (ALSFRS-R) [ Time Frame: 24 months ]
2. Treatment-related change in cognitive function by Edinburgh Cognitive and Behavioral Assessment (ECAS) score [ Time Frame: 24 months ]
3. Treatment-related change in respiratory function by seated forced vital capacity (FCV) [ Time Frame: 24 months ]
4. Treatment-related change in quality of life by ALSSQOL-R score [ Time Frame: 24 months ]
5. Treatment-related change in disease severity by transcranial magnetic stimulation (TMS) response [ Time Frame: 24 months ]
6. Peak Cu(II)ATSM plasma concentration following administration of a single dose based on blood draws taken at 1, 2, 4, 8 and 24 hours after dosing [ Time Frame: 12 months ]
7. Area under the Cu(II)ATSM plasma concentration versus time curve (AUC) following administration of a single dose based on blood draws taken at 1, 2, 4, 8 and 24 hours after dosing [ Time Frame: 12 months ]
8. Treatment-related change in respiratory function by sniff nasal pressure (SNP) test [ Time Frame: 24 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed informed consent prior to initiation of any study-specific procedures;
• Familial or sporadic ALS/MND defined as clinically possible, probable, or definite by Awaji-shima Consensus Recommendations;
• First ALS/MND symptoms occurred no more than 2 years prior to screening visit;
• Seated FVC ≥ 70% and SNP ≥ 50% of predicted value;
• Not taking riluzole or on a stable dose of riluzole for at least 4 weeks prior to screening visit (participants are not allowed to start taking riluzole during the study);
• Age between 18 and 75 years at time of informed consent;
• Patient has a competent caregiver who can and will be responsible for administration of study drug;

• Adequate bone marrow reserve, renal and liver function:

  • absolute neutrophil count ≥ 1500/µL
  • lymphocyte count < 48%
  • platelet count ≥ 150,000/µL
  • hemoglobin ≥ 11 g/dL
  • creatinine clearance ≥ 60 mL/min (Cockroft & Gault formula)
  • ALT and/or AST ≤ 2 x ULN
  • total bilirubin ≤ 1.5 x ULN
  • serum albumin ≥ 2.8 g/dL
• Women and men with partners of childbearing potential must take effective contraception while on study and women of childbearing potential must have a negative pregnancy test and be non-lactating at screening

Exclusion Criteria:

• Inability to swallow oral medications or presence of GI disorder deemed to jeopardize intestinal absorption of Cu(II)ATSM
• Dependence of mechanical ventilation (non-invasive or invasive) for any part of day or night
• Exposure to any other investigational agent within 3 months or two investigational agents within 6 months prior to screening visit
• Active GI disease (except gastrointestingal reflux disease) within 30 days of screening visit
• Known immune compromising illness or treatment

• Presence of any of the following clinical conditions

  • drug abuse or alcoholism
  • unstable cardiac, pulmonary, renal, hepatic, endocrine or hematologic disorder
  • active infectious disease
  • AIDS or AIDS-related complex
  • current malignancy
  • unstable psychiatric illness, defined as psychosis or untreated major depression within 90 days of screening visit
  • neuromuscular disease other than ALS/MND
• Dementia that may affect either outcome measures or patient understanding and/or compliance with study requirements and procedures
• Use of anticoagulants at therapeutic doses within 7 days prior to screening visit
• Current use of strong inducers or inhibitors of CYPs 2C19 and 2D6

Contacts and Locations

Locations

Australia, New South Wales

Macquarie University

Sydenham, New South Wales, Australia, 2109

Australia, Victoria

Calvary Health Care Bethlehem

Caulfield, Victoria, Australia, 3162

Sponsors and Collaborators

Collaborative Medicinal Development Pty Limited

Investigators

• Principal Investigator: Dominic Rowe, MD; Macquarie University

More Information

• Responsible Party: Collaborative Medicinal Development Pty Limited
• ClinicalTrials.gov Identifier: NCT02870634
• Other Study ID Numbers: CMD-2016-001
• First Posted: August 17, 2016
• Last Update Posted: March 17, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Copper; Trace Elements; Micronutrients; Physiological Effects of Drugs