The feasibility of using a subtherapeutic dose of piracetam as a marker of adherence to therapy

This study with healthy volunteers will test a subtherapeutic dose of piracetam
as an adherence marker to assess the feasibility of its use in a multicenter,
randomized, double-blind, placebo-controlled study of the efficacy of
dexamfetamine in cocaine use disorder (CUD) with comorbid opioid use disorder
(REDUCE-trial).

Adherence to the study medication in the REDUCE-trial will be assessed by
urinanalysis twice weekly for the presence of dexamfetamine. To determine
adherence in the placebo group, the tablets must be formulated with a marker
detectable in urine. It is necessary to assess adherence in the REDUCE-trial
since stimulants will be provided to patients who are dependent on stimulants.
Moreover, monitoring adherence ensures that efficacy is established when the
medication is taken at the correct dose and frequency.[1] Non-adherence to
study medication is especially a problem in trials involving the addicted
population, with 10% of participants never taking a dose.[2] In addition,
relatively low adherence rates (39-42%) are common for this population.[3][4]
Efficacy and safety effects may be underestimated as a result of nonadherence
to study medication. Since adherence to placebo was found to be a predictor of
better treatment outcomes, it is important to assess this as well.[5]

Several markers for assessing medication adherence are described in the
literature.[1][7-12] However, none of these previously used markers were
eligible for use within the clinical trial design. First, the measurement of
adherence for some markers was based on urine staining (methylene blue, phenol
red, fluorescein, phenazopyridine) that would be visible to patients enrolled
in the trial. Second, some markers (riboflavin, quinine) are interfered with by
dietary or vitamin intake.[1] In addition, some markers are limited by the
occurrence of side effects (phenobarbital).[10][11] Finally, the long half-life
of the adherence markers bromide and digoxin would not fit the twice weekly
urinalysis, where non-compliance of several days would be masked.[7-9]
Therefore, a suitable marker for the REDUCE-trial was searched.

The ideal marker is nontoxic and potentially detectable in urine at a
subtherapeutic dose. Therefore, a drug with a relatively high therapeutic dose,
high bioavailability, high unchanged renal clearance and low hepatic metabolism
is favourable. Thus, detectable amounts in urine at subtherapeutic dose would
be likely. Moreover, the half-live of the marker must match the twice weekly
assessments of adherence. Of all the authorised drugs in the Netherlands,
piracetam was found to meet the most of the criteria. Piracetam is a
well-tolerated therapy and registered in the Netherlands for the treatment of
vertigo. Daily therapeutic intake is 2400 mg with complete bioavailability, no
hepatic metabolism and a renal clearance of about 90%.[13] The likelihood of
interference with prescribed piracetam is low, as only 740 patients used the
drug in the Netherlands in 2021.[14]

The subtherapeutic dose of piracetam was calculated using the EMA guidelines on
shared manufacturing facilities.[15] This guideline contains acceptance limits
of cross-contamination between drugs in multipurpose manufacturing processes.
These limits are based on the absence of a therapeutic or toxicological effect
of the residues of an active drug.[15] The permitted daily exposure (PDE) is
calculated using all available pharmacological and toxicological data,
including both non-clinical and clinical data, to derive safe thresholds. The
PDE represents a substance-specific dose that is unlikely to cause adverse
effects if a person is exposed to or below this dose for a lifetime. The PDE
for piracetam was calculated to be 8 mg (Appendix I). As patients in the
REDUCE-trial receive one, two or three placebo tablets per day, the intention
is to add 2.5 mg of piracetam to the placebo tablets. If the urine
concentration of piracetam known in the literature at daily intake of 800 mg is
extrapolated to 2.5 mg, a measurable urine concentration of 200 ng/ml is
expected.[16] However, it should first be confirmed in healthy volunteers
whether detectable piracetam concentrations are actually excreted in the urine.

The references can be found on pages 25-26 of the study protocol.

To assess the feasibility of using a subtherapeutic dose of piracetam as a
marker of adherence to therapy by determining whether this subtherapeutic dose
produces a detectable concentration in the urine

Prospective, single center, open-label, uncontrolled study in 10 healthy
volunteers who will receive various subtherapeutic doses of piracetam

All included participants will administer the investigational product once
weekly according to the following scheme:

Week 1 (day 1): 7.5 mg (6 tablets)
Week 2 (day 1): 5 mg (4 tablets)
Week 3 (day 1): 2.5 mg (2 tablets)
Week 4 (day 1): 1.25 mg (1 tablet)

Urine samples will be collected 24 and 72 hours after administration of the
weekly dose

As described under E9, the risks to participants within this study are
negligible.

Participants themselves do not benefit from taking part in this study. But by
participating, participants help to reliably investigate whether a drug works
well in a study in the future. This may act as motivation for participants to
participate in the study and be perceived as a benefit. Taking part in this
study may have disadvantages. The burden of this study includes 10 visits to
the treatment site. The intake of six and four tablets respectively (in week 1
and week 2) may be perceived as burdensome by the participants. In addition,
the participants may find the submission of urine unhygienic or uncomfortable.
Participating in the study will cost participants extra time and they will have
to follow the arrangements associated with the study.