Clinical trial NCT02639975: "First-in-human" Study To Assess the Safety and Tolerability of PBF-677 in Healthy Volunteers
Official title: Randomized, Double Blind, Placebo Controlled "First-in-human" Study To Assess the Safety and Tolerability of Single Ascending Oral Doses of PBF-677 ( 100 mg, 200 mg, 400 mg and 600 mg ) in Healthy Young Male Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glaucoma
Keywords: Adenosine A3 receptor antagonist
Lead sponsor: Palobiofarma SL
Sponsor class: INDUSTRY
First posted: 2015-12-28
Enrollment: 32
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The proposed trial a "Randomized, Double Blind, Placebo Controlled "first in-human" Study to Assess the Safety and Tolerability of Single Ascending Oral Doses of PBF-677 in Male Healthy Volunteers" (Protocol Code No:CUNFI-1509 EudraCT No:2015-003546-57) will be a single-centre, randomized, double-blind, dose escalation study without therapeutic benefit, in which PBF-677 will be administered as single, oral, ascending-dose to volunteers.

Up to four different rising doses (100 mg, 200 mg, 400 mg and 600 mg) will be tested in groups of 8 participants; in each dose level participants will be randomized to active drug or placebo in a 6:2 fashion. As this will be the first time that PBF-677 in going to be administered to humans, as a safety measure a stepwise drug administration will be performed in each cohort. The volunteers of each cohort will be divided in 3 blocks/subgroups: Initially, one volunteer will receive active drug (subgroup 1). After 48h of safety and tolerability assessment, a second subgroup of 3 volunteers will receive 2 active drug and 1 placebo and after further 48h of safety and tolerability assessments a third subgroup of 4 volunteers will receive 3 active drug and 1 placebo. After evaluation of safety, parameters of corresponding dose level the process will replicate one week afterwards in the following dosages.

The principal variable safety and tolerability of PBF-677 will be evaluated with physical records (Electrocardiogram (ECG), vital signs, blood chemistry and haematology, conducted before, during and after study course). Assessment of the pharmacokinetic profile (Maximum plasma concentration of the drug (peak) after single dose (Cmax),Time necessary to reach Cmax (tmax), Area under the time-concentration curve to "zero" to time "t" (AUC0t), and Elimination half-life (t1/2) of PBF-677 will be included as secondary variable.


Eligibility criteria: Inclusion Criteria:

1. Healthy male subjects, 18-45 years (inclusive) of age at the time of enrollment.
2. Males should agree to abstain from sexual intercourse with a female partner or agree to use a condom with spermicide, in addition to having their female partner use some contraceptive measures as oral contraceptive drugs, intrauterine hormonal contraception, or cervical caps until 28 days post-administration.
3. Clinically acceptable blood pressure and pulse rate in supine and standing position (SBP between 140-100 mm Hg/ DBP between 90-50 mm Hg / HR between 100-50 bpm). Blood pressure and pulse will be measured after a minimum of 3 minutes of resting.
4. Body weight within normal range (Quetelet's index between 19 and 26) expressed as weight (kg) / height (m2).
5. Able to understand the nature of the study and comply with all their requirements.
6. Free acceptance to participate in the study by obtains signed informed consent form approved by the Ethics Committee (CEIC).

Exclusion Criteria:

1. History of serious adverse reactions or hypersensitivity to any drug.
2. Presence or history of allergies requiring acute or chronic treatment (except seasonal allergic rhinitis).
3. Background or clinical evidence of chronic diseases.
4. Acute illness two weeks before drug administration.
5. Having undergone major surgery during the previous 6 months.
6. Smokers (refrained from any tobacco usage, including smokeless tobacco, nicotine patches, etc., for 6 months prior to the administration of the study medication).
7. History of alcohol dependence or drug abuse in the last 5 years or daily consumption of alcohol \> 40 g or high consumption of stimulating beverages (\> 5 coffees, teas or coca cola drinks/ day).
8. Abnormal physical findings of clinical significance at the screening examination or baseline which would interfere with the objectives of the study.
9. Need of any prescription medication within 14 days prior to the administration of the investigational drug and non prescription medication or herbal medicines within 7 days prior to the administration of the drug. Paracetamol (acetaminophen) is allowed, at doses up to 1 g daily, at the investigator discretion.
10. Participation in other clinical trials during the previous 90 days in which an investigational drug or a commercially available drug was tested.
11. Having donated blood during 3 months period before inclusion in the study.
12. Existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the drug, i.e. impaired renal or hepatic function, diabetes mellitus, cardiovascular abnormalities, chronic symptoms of pronounced constipation or diarrhea or conditions associated with total or partial obstruction of the urinary tract
13. 12 lead ECG obtained at screening with PR ≥ 220 msec, QRS ≥120 msec and QTc ≥ 440 msec, bradycardia (\<50 bpm) or clinically significant minor ST wave changes or any other abnormal changes on the screening ECG that would interfere with measurement of the QT interval.
14. Symptoms of a significant somatic or mental illness in the four week period preceding drug administration.
15. History of hepatitis HBV and / or HCV and / or positive serology results which indicate the presence of hepatitis B surface antigen and / or detectable HCV ribonucleic acid (RNA).
16. Positive results from the HIV serology.
17. Clinically significant abnormal laboratory values (as determined by the Principal Investigator) at the screening evaluation.
18. Positive results of the drugs at screening period or the day before starting treatment period. A minimum list of 6 drugs will be screened for inclusion: Amphetamines, Cocaine, Ethanol, Opiates, Cannabinoids and Benzodiazepines (positive results may be repeated at the discretion of the Principal Investigator).
19. Known hypersensitivity to the study drug or the composition of the galenical form.
20. History of psychiatric diseases or epileptic seizures.
21. Pill swallowing difficulties.

Primary outcomes:
measure: Number of Adverse events
timeFrame: 1 week
Secondary outcomes:
measure: Number of Participants With Abnormal Laboratory Values
timeFrame: 5-7 days post administration
measure: Electrocardiogram (EKG)
timeFrame: [pre-dose], [+ 40min], [+ 1.5h], [+ 3h], [+ 24h] and Days (5-7) post-medication
measure: Vital signs
timeFrame: [pre-dose], [+ 20 min], [+ 60min], [+ 2h], [+ 4h], [+ 8h], [+ 12h] , [+ 24h] and Days (5-7) post-medication
measure: Physical examination
timeFrame: At day-1 (predose), at + 24h post-drug administration and at the follow-up (5-7) days
measure: Maximum plasma concentration of PBF-677 (peak) after single dose (Cmax)
timeFrame: 0-24 h post dose
measure: Time necessary to reach Maximum plasma concentration of PBF-677 (Tmax)
timeFrame: 0-24 h post dose
measure: Area under the time-concentration curve to "zero" to time "t" (AUC0t)
timeFrame: 0-24 h post dose
measure: Elimination half-life (t1/2) of PBF-677
timeFrame: 0-24 h post dose
Other outcomes:
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