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The aim of this study is to test a subtherapeutic dose of piracetam in healthy volunteers as a marker of adherence to therapy to assess the feasibility of its use in a multicentre, randomised, double-blind, placebo-controlled study of the efficacy of dexamphetamine in cocaine dependence (CUD) with comorbid opioid addiction (REDUCE study). Several markers for assessing adherence have been described in the literature. However, none of these markers qualified for use within the targeted patient population. Therefore, a suitable adherence marker was sought specifically for the study design of the REDUCE trial. Since within the REDUCE trial urine is submitted biweekly by participants for measuring cocaine use, the adherence marker will also be determined in this matrix. The most suitable marker seems to be piracetam. However, within this study with healthy volunteers, it will first have to be confirmed whether detectable concentrations of piracetam are actually excreted in the urine.
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 clinical 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 dietaryor 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 clinical 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 clinical 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.
References
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Piracetam arm (single arm) | Experimental | The single to take once weekly doses of 7.5 mg, 5 mg, 2.5 mg and 1.25 mg piracetam consecutively. Urine was collected 24 and 72 hours after the weekly doses were taken. It was chosen to administer all these doses in each healthy volunteer to account for inter-individual differences in urine concentrations, as these concentrations depend on individual characteristics such as volume intake and renal function. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Piracetam | Drug | Subtherapeutic dose of piracetam (once-weekly doses of 7.5 mg, 5 mg, 2.5 mg and 1.25 mg) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Primary Objective (detectability of piracetam in urine) | 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. | 24 hours after weekly ingestion of weekly dosage |
| Measure | Description | Time Frame |
|---|---|---|
| Secondary Objective (piracetam concentration after nonadherence) | To determine the piracetam urine concentrations after nonadherence of two days. | 72 hours after weekly ingestion of weekly dosage |
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Inclusion Criteria:
Exclusion Criteria:
Current prescribed treatment with piracetam;
Pregnant or breastfeeding;
Criteria regarding the following contra-indications for piracetam:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Anke Leeuwerik, MSc | Contact | 0031624321167 | a.leeuwerik@nki.nl |
| Name | Affiliation | Role |
|---|---|---|
| Alwin Huitema, Prof. Dr. | The Netherlands Cancer Institute | Principal Investigator |
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Providing raw participant data to other researchers, for this particular study, will not be of general interest. However, all measured urine concentrations will be published and can be accessed by other researchers in this way.
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| ID | Term |
|---|---|
| D055118 | Medication Adherence |
| ID | Term |
|---|---|
| D010349 | Patient Compliance |
| D010342 | Patient Acceptance of Health Care |
| D000074822 | Treatment Adherence and Compliance |
| D015438 | Health Behavior |
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| ID | Term |
|---|---|
| D010889 | Piracetam |
| ID | Term |
|---|---|
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 |
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Prospective, single center, open-label, uncontrolled study in 10 healthy volunteers who will receive various subtherapeutic doses of piracetam.
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| D001519 | Behavior |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |