Primary Objectives:* To evaluate the effects of therapeutic and supratherapeutic plasma levels of arimoclomol on the heart rate-corrected QT interval (QTc).Secondary Objectives:* To evaluate the effect of arimoclomol on other ECG parameters: heart…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
protein aggregation and protein misfolding diseases (lysosomal storage diseases and neuromuscular disorders such as ALS
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
* Placebo-corrected change-from-baseline QTcF (**QTcF).
Pharmacokinetic Endpoints:
The pharmacokinetic parameters calculated for arimoclomol, M2 and M105 in
plasma are:
* AUC0-inf: area under the arimoclomol, M2 and M105 plasma-concentration-time
curves from zero to infinity
* AUC0-t: area under the arimoclomol, M2 and M105 plasma-concentration-time
curves from zero to last quantifiable plasma concentration
* AUC0-8: area under the arimoclomol, M2 and M105 plasma-concentration-time
curves from zero to 8 hours post-dose (Day 1 only)
* AUC%extrap: percent extrapolated of total AUC0-inf
* Cmax: maximum observed plasma concentration of arimoclomol, M2 and M105
* Tmax: time at which maximum observed plasma concentrations of arimoclomol, M2
and M105 occurred (Day 1 only)
* t*: terminal elimination half-life for arimoclomol, M2 and M105
* CL/F (oral clearance) (for arimoclomol only)
* Vz/F: apparent volume of distribution for arimoclomol
* MR (metabolic ratio, defined as AUCmetabolite/AUCarimoclomol)
Safety Endpoints:
* Adverse events
* Absolute values and changes from baseline in clinical safety laboratory test
values, vital signs, weight, and ECG parameter values
* Potentially clinically significant (PCS) clinical safety laboratory test
values, vital signs, weight changes, and ECG parameter values
Secondary outcome
Secondary Endpoints:
* Change-from-baseline QTcF, HR, PR, QRS intervals (*QTcF, *HR, *PR, and *QRS)
* Placebo-corrected change-from-baseline HR, PR, and QRS (**HR, **PR, **QRS)
* Categorical outliers for QTcF, HR, PR, and QRS
* Frequency of treatment-emergent changes of T-wave morphology and U-waves
presence
Background summary
Arimoclomol is an orally available small molecule that crosses the blood brain
barrier and amplifies the cellular production of HSPs, in particular HSP70,
through the activation of heat shock factor-1 (HSF-1), the major regulator of
HSP gene transcription (Kieran et al., 2004; Neef, Jaeger, & Thiele, 2011).
Heat shock proteins are part of a natural defence system and function by
preventing protein misfolding under cellular stress and promoting proper
lysosomal homeostasis. Thus, arimoclomol has a novel mechanism of action and
may be used to treat conditions that involve misfolded proteins and/or
dysfunctional lysosomes, such as LSDs (e.g. NPC and GD) and neuromuscular
disorders (e.g. ALS and sIBM) (Ingemann & Kirkegaard, 2014; Kalmar &
Greensmith, 2017).
Study objective
Primary Objectives:
* To evaluate the effects of therapeutic and supratherapeutic plasma levels of
arimoclomol on the heart rate-corrected QT interval (QTc).
Secondary Objectives:
* To evaluate the effect of arimoclomol on other ECG parameters: heart rate
(HR), PR and QRS interval and
T-wave morphology.
* To demonstrate sensitivity of the trial to detect a small QT effect using
moxifloxacin as a positive control.
Safety Objectives:
* To evaluate the safety and tolerability of multiple therapeutic 124 (200) mg
t.i.d. (372 (600) mg/day) and supratherapeutic 372 (600) mg t.i.d. (1116 (1800)
doses of arimoclomol in healthy subjects.
Pharmacokinetic Objectives:
* To assess the PK of arimoclomol and metabolites M2 and M105 following
administration of multiple therapeutic and supratherapeutic doses of
arimoclomol.
Study design
This is a randomised, partial double-blind trial in healthy subjects, which
will be conducted as a placebo- and positive-controlled, multiple dose, 4-way
crossover trial using moxifloxacin as a positive control. Arimoclomol will be
studied at both a therapeutic and a supratherapeutic dose level. The treatment
with arimoclomol and placebo will be double-blinded, whereas the treatment with
moxifloacin will be open-labeled.
See chapter 4 Trial Design of the CSP
Intervention
Thirty-two (32) subjects will be randomised to ensure 26 evaluable subjects per
group. Subjects participating in the trial will attend the clinical trial site
for screening, 4 in-house periods (Treatment Periods 1-4) and a follow-up
visit, i.e. 6 visits in total, see Figure 4 1 of the CSP. The total trial
duration will be between 12 to 20 weeks.
Each treatment period will consist of dosing 3 times a day (t.i.d) for 2 days
on Days 1-2 and a single dosing in the morning on Day 3. Each treatment period
will be separated by 17 (+2) days.
The subjects will be allocated to the following four treatments in separate
periods in a randomised sequence:
* Treatment A: Arimoclomol, therapeutic dose level (124 (200) mg t.i.d)
* Treatment B: Arimoclomol, supratherapeutic dose level (372 (600) mg t.i.d)
* Treatment C: Placebo
* Treatment D: Moxifloxacin (positive control)
Subjects will be randomised in an equal ratio to one of 12 treatment sequences.
Each treatment sequence will comprise all 4 treatments:
* ABCD, BADC, CDAB, DCBA, ACDB, BDCA, CABD, DBAC, ADBC, BCAD, CBDA, DACB
Study burden and risks
Since the study is being executed in healthy volunteers, there are no
anticipated benefits of the IMP. Please see the IMPD for further information.
Ole Maaløes Vej 3 Ole Maaløes Vej 3
Copenhagen N DK-2200
DK
Ole Maaløes Vej 3 Ole Maaløes Vej 3
Copenhagen N DK-2200
DK
Listed location countries
Age
Inclusion criteria
1. The subject is able to read and understand the Subject Information Sheet and
Informed Consent Form.
2. The subject has signed the trial-specific Informed Consent Form.
3. The subject is a man
4. The subject must:
a. remain sexually abstinent, when this is in line with his preferred and usual
lifestyle OR
b. engage exclusively in same-sex relationships OR
c. agree to avoid impregnating his partner from the Screening Visit until 2
weeks after the last dose of IMP, AND
d. agree to use highly effective contraception methods as described in Appendix
4 from the Screening Visit until 2 weeks after dosing if his female partner is
of childbearing potential
e. not donate sperm until *3 months after the last dose of IMP
Exclusion criteria
1. The subject has taken any prescription or non-prescription medication <1
week prior to the first IMP dosing or *5 half-lives prior to the Screening
Visit for any medication taken.
2. The subject has significant alcohol consumption, defined as an alcohol
intake >21 units per week, or substance use (excluding nicotine or caffeine)
deemed significant by the investigator, or a history of substance abuse (DSM-5®
criteria) <12 months prior to the Screening Visit. A unit of alcohol is defined
as 250 mL of lager/beer, 100 mL of wine, or 25 mL of spirits
3. The subject has taken any investigational medicinal product within 3 months
prior to the first IMP dosing.
4. The subject has taken any nutritional or dietary supplements, herbal
preparations, or vitamins within 7 days prior to the first IMP dosing.
5. The subject has previously been dosed with arimoclomol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000415-68-NL |
| CCMO | NL73001.056.20 |